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Psychiatry Online

  • Winter 2024 | VOL. 36, NO. 1 CURRENT ISSUE pp.A5-81

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Case Study 1: A 55-Year-Old Woman With Progressive Cognitive, Perceptual, and Motor Impairments

  • Scott M. McGinnis , M.D. ,
  • Andrew M. Stern , M.D., Ph.D. ,
  • Jared K. Woods , M.D., Ph.D. ,
  • Matthew Torre , M.D. ,
  • Mel B. Feany , M.D., Ph.D. ,
  • Michael B. Miller , M.D., Ph.D. ,
  • David A. Silbersweig , M.D. ,
  • Seth A. Gale , M.D. ,
  • Kirk R. Daffner , M.D.

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CASE PRESENTATION

A 55-year-old right-handed woman presented with a 3-year history of cognitive changes. Early symptoms included mild forgetfulness—for example, forgetting where she left her purse or failing to remember to retrieve a take-out order her family placed—and word-finding difficulties. Problems with depth perception affected her ability to back her car out of the driveway. When descending stairs, she had to locate her feet visually in order to place them correctly, such that when she carried her dog and her view was obscured, she had difficulty managing this activity. She struggled to execute relatively simple tasks, such as inserting a plug into an outlet. She lost the ability to type on a keyboard, despite being able to move her fingers quickly. Her symptoms worsened progressively for 3 years, over which time she developed a sad mood and anxiety. She was laid off from work as a nurse administrator. Her family members assumed responsibility for paying her bills, and she ceased driving.

Her past medical history included high blood pressure, Hashimoto’s thyroiditis with thyroid peroxidase antibodies, remote history of migraine, and anxiety. Medications included mirtazapine, levothyroxine, calcium, and vitamin D. She had no history of smoking, drinking alcohol, or recreational drug use. There was no known family history of neurologic diseases.

What Are Diagnostic Considerations Based on the History? How Might a Clinical Examination Help to Narrow the Differential Diagnosis?

Insidious onset and gradual progression of cognitive symptoms over the course of several years raise concern for a neurodegenerative disorder. It is helpful to consider whether or not the presentation fits with a recognized neurodegenerative clinical syndrome, a judgment based principally on familiarity with syndromes and pattern recognition. Onset of symptoms before age 65 should prompt consideration of syndromes in the spectrum of frontotemporal dementia (FTD) and atypical (nonamnesic) presentations of Alzheimer’s disease (AD) ( 1 , 2 ). This patient’s symptoms reflect relatively prominent early dysfunction in visual-spatial processing and body schema, as might be observed in posterior cortical atrophy (PCA), although the history also includes mention of forgetfulness and word-retrieval difficulties. A chief goal of the cognitive examination would be to survey major domains of cognition—attention, executive functioning, memory, language, visual-spatial functioning, and higher somatosensory and motor functioning—to determine whether any domains stand out as more prominently affected. In addition to screening for evidence of focal signs, a neurological examination in this context should assess for evidence of parkinsonism or motor neuron disease, which can coexist with cognitive changes in neurodegenerative presentations.

The patient’s young age and history of Hashimoto’s thyroiditis might also prompt consideration of Hashimoto’s encephalopathy (HE; also known as steroid-responsive encephalopathy), associated with autoimmune thyroiditis. This syndrome is most likely attributable to an autoimmune or inflammatory process affecting the central nervous system. The time course of HE is usually more subacute and rapidly progressive or relapsing-remitting, as opposed to the gradual progression over months to years observed in the present case ( 3 ).

The patient’s mental status examination included the Montreal Cognitive Assessment (MoCA), a brief global screen of cognition ( 4 ), on which she scored 12/30. There was evidence of dysfunction across multiple cognitive domains ( Figure 1 ). She was fully oriented to location, day, month, year, and exact date. When asked to describe a complex scene from a picture in a magazine, she had great difficulty doing so, focusing on different details but having trouble directing her saccades to pertinent visual information. She likewise had problems directing her gaze to specified objects in the room and problems reaching in front of her to touch target objects in either visual field. In terms of other symptoms of higher order motor and somatosensory functioning, she had difficulty demonstrating previously learned actions—for example, positioning her hand correctly to pantomime holding a brush and combing her hair. She was confused about which side of her body was the left and which was the right. She had difficulty with mental calculations, even relatively simple ones such as “18 minus 12.” In addition, she had problems writing a sentence in terms of both grammar and the appropriate spacing of words and letters on the page.

FIGURE 1. Selected elements of a 55-year-old patient’s cognitive examination at presentation a

a BNT-15=Boston Naming Test (15-Item); MoCA=Montreal Cognitive Assessment.

On elementary neurologic examination she had symmetrically brisk reflexes, with spread. She walked steadily with a narrow base, but when asked to pass through a doorway she had difficulty finding her way through it and bumped into the door jamb. Her elemental neurological examination was otherwise normal, including but not limited to brisk, full-amplitude vertical eye movements, normal visual fields, no evidence of peripheral neuropathy, and no parkinsonian signs such as slowness of movement, tremor, or rigidity.

How Does the Examination Contribute to Our Understanding of Diagnostic Considerations? What Additional Tests or Studies Are Indicated?

The most prominent early symptoms and signs localize predominantly to the parietal association cortex: The patient has impairments in visual construction, ability to judge spatial relationships, ability to synthesize component parts of a visual scene into a coherent whole (simultanagnosia or asimultagnosia), impaired visually guided reaching for objects (optic ataxia), and most likely impaired ability to shift her visual attention so as to direct saccades to targets in her field of view (oculomotor apraxia or ocular apraxia). The last three signs constitute Bálint syndrome, which localizes to disruption of dorsal visual networks (i.e., dorsal stream) with key nodes in the posterior parietal and prefrontal cortices bilaterally ( 5 ). She has additional salient symptoms and signs suggesting left inferior parietal dysfunction, including ideomotor limb apraxia and elements of Gerstmann syndrome, which comprises dysgraphia, acalculia, left-right confusion, and finger agnosia ( 6 ). Information was not included about whether she was explicitly examined for finger agnosia, but elements of her presentation suggested a more generalized disruption of body schema (i.e., her representation of the position and configuration of her body in space). Her less prominent impairment in lexical-semantic retrieval evidenced by impaired confrontation naming and category fluency likely localizes to the language network in the left hemisphere. Her impairments in attention and executive functions have less localizing value but would plausibly arise in the context of frontoparietal network dysfunction. At this point, it is unclear whether her impairment in episodic memory mostly reflects encoding and activation versus a rapid rate of forgetting (storage), as occurs in temporolimbic amnesia. Regardless, it does not appear to be the most salient feature of her presentation.

This localization, presenting with insidious onset and gradual progression, is characteristic of a PCA syndrome. If we apply consensus clinical diagnostic criteria proposed by a working group of experts, we find that our patient has many of the representative features of early disturbance of visual functions plus or minus other cognitive functions mediated by the posterior cerebral cortex ( Table 1 ) ( 7 ). Some functions such as limb apraxia also occur in corticobasal syndrome (CBS), a clinical syndrome defined initially in association with corticobasal degeneration (CBD) neuropathology, a 4-repeat tauopathy characterized by achromatic ballooned neurons, neuropil threads, and astrocytic plaques. However, our patient lacks other suggestive features of CBS, including extrapyramidal motor dysfunction (e.g., limb rigidity, bradykinesia, dystonia), myoclonus, and alien limb phenomenon ( Table 1 ) ( 8 ).

a Consensus diagnostic criteria for posterior cortical atrophy per Crutch et al. ( 7 ) require at least three cognitive features and relative sparing of anterograde memory, speech-nonvisual language functions, executive functions, behavior, and personality. Diagnostic criteria for probable corticobasal syndrome per Armstrong et al. ( 8 ) require asymmetric presentation of at least two motor features and at least two higher cortical features. AD=Alzheimer’s disease; CBD=corticobasal degeneration; FDG-PET=[ 18 ]F-fluorodexoxyglucose positron emission tomography; JCD=Jakob-Creutzfeldt disease; LBD=Lewy body disease; PSP=progressive supranuclear palsy; SPECT=single-photon emission computed tomography; TDP=TDP–43 proteinopathy.

TABLE 1. Clinical features and neuropathological associations of posterior cortical atrophy and corticobasal syndrome a

In addition to a standard laboratory work-up for cognitive impairment, it is important to determine whether imaging of the brain provides evidence of neurodegeneration in a topographical distribution consistent with the clinical presentation. A first step in most cases would be to obtain an MRI of the brain that includes a high-resolution T 1 -weighted MRI sequence to assess potential atrophy, a T 2 /fluid-attenuated inversion recovery (FLAIR) sequence to assess the burden of vascular disease and rule out less likely etiological considerations (e.g., infection, autoimmune-inflammatory, neoplasm), a diffusion-weighted sequence to rule out subacute infarcts and prion disease (more pertinent to subacute or rapidly progressive cases), and a T 2 *-gradient echo or susceptibility weighted sequence to examine for microhemorrhages and superficial siderosis.

A lumbar puncture would serve two purposes. First, it would allow for the assessment of inflammation that might occur in HE, as approximately 80% of cases have some abnormality of CSF (i.e., elevated protein, lymphocytic pleiocytosis, or oligoclonal bands) ( 9 ). Second, in selected circumstances—particularly in cases with atypical nonamnesic clinical presentations or early-onset dementia in which AD is in the neuropathological differential diagnosis—we frequently pursue AD biomarkers of molecular neuropathology ( 10 , 11 ). This is most frequently accomplished with CSF analysis of amyloid-β-42, total tau, and phosphorylated tau levels. Amyloid positron emission tomography (PET) imaging, and most recently tau PET imaging, represent additional options that are approved by the U.S. Food and Drug Administration for clinical use. However, insurance often does not cover amyloid PET and currently does not reimburse tau PET imaging. [ 18 ]-F-fluorodeoxyglucose (FDG) PET and perfusion single-photon emission computed tomography imaging may provide indirect evidence for AD neuropathology via a pattern of hypometabolism or hypoperfusion involving the temporoparietal and posterior cingulate regions, though without molecular specificity. Pertinent to this case, a syndromic diagnosis of PCA is most commonly associated with underlying AD neuropathology—that is, plaques containing amyloid-β and neurofibrillary tangles containing tau ( 12 – 15 ).

The patient underwent MRI, demonstrating a minimal burden of T 2 /FLAIR hyperintensities and some degree of bilateral parietal volume loss with a left greater than right predominance ( Figure 2A ). There was relatively minimal medial temporal volume loss. Her basic laboratory work-up, including thyroid function, vitamin B 12 level, and treponemal antibody, was normal. She underwent a lumbar puncture; CSF studies revealed normal cell counts, protein, and glucose levels and low amyloid-β-42 levels at 165.9 pg/ml [>500 pg/ml] and elevated total and phosphorylated tau levels at 1,553 pg/ml [<350 pg/ml] and 200.4 pg/ml [<61 pg/ml], respectively.

FIGURE 2. MRI brain scan of the patient at presentation and 4 years later a

a Arrows denote regions of significant atrophy.

Considering This Additional Data, What Would Be an Appropriate Diagnostic Formulation?

For optimal clarity, we aim to provide a three-tiered approach to diagnosis comprising neurodegenerative clinical syndrome (e.g., primary amnesic, mixed amnesic and dysexecutive, primary progressive aphasia), level of severity (i.e., mild cognitive impairment; mild, moderate or severe dementia), and predicted underlying neuropathology (e.g., AD, Lewy body disease [LBD], frontotemporal lobar degeneration) ( 16 ). This approach avoids problematic conflations that cause confusion, for example when people equate AD with memory loss or dementia, whereas AD most strictly describes the neuropathology of plaques and tangles, regardless of the patient’s clinical symptoms and severity. This framework is important because there is never an exclusive, one-to-one correspondence between syndromic and neuropathological diagnosis. Syndromes arise from neurodegeneration that starts focally and progresses along the anatomical lines of large-scale brain networks that can be defined on the basis of both structural and functional connectivity, a concept detailed in the network degeneration hypothesis ( 17 ). It is important to note that neuropathologies defined on the basis of specific misfolded protein inclusions can target more than one large-scale network, and any given large-scale network can degenerate in association with more than one neuropathology.

The MRI results in this case support a syndromic diagnosis of PCA, with a posteriorly predominant pattern of atrophy. Given the patient’s loss of independent functioning in instrumental activities of daily living (ADLs), including driving and managing her finances, the patient would be characterized as having a dementia (also known as major neurocognitive disorder). The preservation of basic ADLs would suggest that the dementia was of mild severity. The CSF results provide supportive evidence for AD amyloid plaque and tau neurofibrillary tangle (NFT) neuropathology over other pathologies potentially associated with PCA syndrome (i.e., CBD, LBD, TDP-43 proteinopathy, and Jakob-Creutzfeldt disease) ( 13 , 14 ). The patient’s formulation would thus be best summarized as PCA at a level of mild dementia, likely associated with underlying AD neuropathology.

The patient’s symptoms progressed. One year after initial presentation, she had difficulty locating the buttons on her clothing or the food on her plate. Her word-finding difficulties worsened. Others observed stiffness of her right arm, a new symptom that was not present initially. She also had decreased ability using her right hand to hold everyday objects such as a comb, a brush, or a pen. On exam, she was noted to have rigidity of her right arm, impaired dexterity with her right hand for fine motor tasks, and a symmetrical tremor of the arms, apparent when holding objects or reaching. Her right hand would also intermittently assume a flexed, dystonic posture and would sometime move in complex ways without her having a sense of volitional control.

Four to 5 years after initial presentation, her functional status declined to the point where she was unable to feed, bathe, or dress herself. She was unable to follow simple instructions. She developed neuropsychiatric symptoms, including compulsive behaviors, anxiety, and apathy. Her right-sided motor symptoms progressed; she spent much of the time with her right arm flexed in abnormal postures or moving abnormally. She developed myoclonus of both arms. Her speech became slurred and monosyllabic. Her gait became less steady. She underwent a second MRI of the brain, demonstrating progressive bilateral atrophy involving the frontal and occipital lobes in addition to the parietal lobes and with more left > right asymmetry than was previously apparent ( Figure 2B ). Over time, she exhibited increasing weight loss. She was enrolled in hospice and ultimately passed away 8 years from the onset of symptoms.

Does Information About the Longitudinal Course of Her Illness Alter the Formulation About the Most Likely Underlying Neuropathological Process?

This patient developed clinical features characteristic of corticobasal syndrome over the longitudinal course of her disease. With time, it became apparent that she had lost volitional control over her right arm (characteristic of an alien limb phenomenon), and she developed signs more suggestive of basal ganglionic involvement (i.e., limb rigidity and possible dystonia). This presentation highlights the frequent overlap between neurodegenerative clinical syndromes; any given person may have elements of more than one syndrome, especially later in the course of a disease. In many instances, symptomatic features that are less prominent at presentation but evolve and progress can provide clues regarding the underlying neuropathological diagnosis. For example, a patient with primary progressive apraxia of speech or nonfluent-agrammatic primary progressive aphasia could develop the motor features of a progressive supranuclear palsy (PSP) clinical syndrome (e.g., supranuclear gaze impairment, axial rigidity, postural instability), which would suggest underlying PSP neuropathology (4-repeat tauopathy characterized by globose neurofibrillary tangles, tufted astrocytes, and oligodendroglial coiled bodies).

If CSF biomarker data were not suggestive of AD, the secondary elements of CBS would substantially increase the likelihood of underlying CBD neuropathology presenting with a PCA syndrome and evolving to a mixed PCA-CBS. But the CSF amyloid and tau levels are unambiguously suggestive of AD (i.e., very low amyloid-β-42 and very high p-tau levels), the neuropathology of which accounts for not only a vast majority of PCA presentations but also roughly a quarter of cases presenting with CBS ( 18 , 19 ). Thus, underlying AD appears most likely.

NEUROPATHOLOGY

On gross examination, the brain weighed 1,150 g, slightly less than the lower end of normal at 1,200 g. External examination demonstrated mild cortical atrophy with widening of the sulci, relatively symmetrical and uniform throughout the brain ( Figure 3A ). There was no evidence of atrophy of the brainstem or cerebellum. On cut sections, the hippocampus was mildly atrophic. The substantia nigra in the midbrain was intact, showing appropriate dark pigmentation as would be seen in a relatively normal brain. The remainder of the gross examination was unremarkable.

FIGURE 3. Mild cortical atrophy with posterior predominance and neurofibrillary tangles, granulovacuolar degeneration, and a Hirano body a

a Panel A shows the gross view of the brain, demonstrating mild cortical atrophy with posterior predominance (arrow). Panel B shows the hematoxylin and eosin of the hippocampus at high power, demonstrating neurofibrillary tangles, granulovacuolar degeneration, and a Hirano body.

Histological examination confirmed that the neurons in the substantia nigra were appropriately pigmented, with occasional extraneuronal neuromelanin and moderate neuronal loss. In the nucleus basalis of Meynert, NFTs were apparent on hematoxylin and eosin staining as dense fibrillar eosinophilic structures in the neuronal cytoplasm, confirmed by tau immunohistochemistry (IHC; Figure 4 ). Low-power examination of the hippocampus revealed neuronal loss in the subiculum and in Ammon’s horn, most pronounced in the cornu ammonis 1 (CA1) subfield, with a relatively intact neuronal population in the dentate gyrus. Higher power examination with hematoxylin and eosin demonstrated numerous NFTs, neurons exhibiting granulovacuolar degeneration, and Hirano bodies ( Figure 3B ). Tau IHC confirmed numerous NFTs in the CA1 region and the subiculum. Amyloid-β IHC demonstrated occasional amyloid plaques in this region, less abundant than tau pathology. An α-synuclein stain revealed scattered Lewy bodies in the hippocampus and in the amygdala.

FIGURE 4. Tau immunohistochemistry demonstrating neurofibrillary tangles (staining brown) in the nucleus basalis of Meynert, in the hippocampus, and in the cerebral cortex of the frontal, temporal, parietal, and occipital lobes

In the neocortex, tau IHC highlighted the extent of the NFTs, which were very prominent in all of the lobes from which sections were taken: frontal, temporal, parietal and occipital. Numerous plaques on amyloid-β stain were likewise present in all cortical regions examined. The tau pathology was confined to the gray matter, sparing white matter. There were no ballooned neurons and no astrocytic plaques—two findings one would expect to see in CBD ( Table 2 ).

a AD=Alzheimer’s disease; CBD=corticobasal degeneration; CBS=corticobasal syndrome; PCA=posterior cortical atrophy.

TABLE 2. Neuropathological features of this case compared with a case of corticobasal degeneration a

The case was designated by the neuropathology division as Alzheimer’s-type pathology, Braak stage V–VI (of VI), due to the widespread neocortical tau pathology, with LBD primarily in the limbic areas.

Our patient had AD neuropathology presenting atypically with a young age at onset (52 years old) and a predominantly visual-spatial and corticobasal syndrome as opposed to prominent amnesia. Syndromic diversity is a well-recognized phenomenon in AD. Nonamnesic presentations include not only PCA and CBS but also the logopenic variant of primary progressive aphasia and a behavioral-dysexecutive syndrome ( 20 ). Converging lines of evidence link the topographical distribution of NFTs with syndromic presentations and the pattern of hypometabolism and cortical atrophy. Neuropathological case reports and case series suggest that atypical AD syndromes arise in the setting of higher than normal densities of NFTs in networks subserving the functions compromised, including visual association areas in PCA-AD ( 21 ), the language network in PPA-AD ( 22 ), and frontal regions in behavioral-dysexecutive AD ( 23 ). In a large sample of close to 900 cases of pathologically diagnosed AD employing quantitative assessment of NFT density and distribution in selected neocortical and hippocampal regions, 25% of cases did not conform to a typical distribution of NFTs characterized in the Braak staging scheme ( 24 ). A subset of cases classified as hippocampal sparing with higher density of NFTs in the neocortex and lower density of NFTs in the hippocampus had a younger mean age at onset, higher frequency of atypical (nonamnesic) presentations, and more rapid rate of longitudinal decline than subsets defined as typical or limbic-predominant.

Tau PET, which detects the spatial distribution of fibrillary tau present in NFTs, has corroborated postmortem work in demonstrating distinct patterns of tracer uptake in different subtypes of AD defined by clinical symptoms and topographical distributions of atrophy ( 25 – 28 ). Amyloid PET, which detects the spatial distribution of fibrillar amyloid- β found in amyloid plaques, does not distinguish between typical and atypical AD ( 29 , 30 ). In a longitudinal study of 32 patients at early symptomatic stages of AD, the baseline topography of tau PET signal predicted subsequent atrophy on MRI at the single patient level, independent of baseline cortical thickness ( 31 ). This correlation was strongest in early-onset AD patients, who also tended to have higher tau signal and more rapid progression of atrophy than late-onset AD patients.

Differential vulnerability of selected large-scale brain networks in AD and in neurodegenerative disease more broadly remains poorly understood. There is evidence to support multiple mechanisms that are not mutually exclusive, including metabolic stress to key network nodes, trophic failure, transneuronal spread of pathological proteins (i.e., prion-like mechanisms), and shared vulnerability within network regions based on genetic or developmental factors ( 32 ). In the case of AD, cortical hub regions with high intrinsic functional connectivity to other regions across the brain appear to have high metabolic rates across the lifespan and to be foci of convergence of amyloid-β and tau accumulation ( 33 , 34 ). Tau NFT pathology appears to spread temporally along connected networks within the brain ( 35 ). Patients with primary progressive aphasia are more likely to have a personal or family history of developmental language-based learning disability ( 36 ), and patients with PCA are more likely to have a personal history of mathematical or visuospatial learning disability ( 37 ).

This case highlights the symptomatic heterogeneity in AD and the value of a three-tiered approach to diagnostic formulation in neurodegenerative presentations. It is important to remember that not all AD presents with amnesia and that early-onset AD tends to be more atypical and to progress more rapidly than late-onset AD. Multiple lines of evidence support a relationship between the burden and topographical distribution of tau NFT neuropathology and clinical symptomatology in AD, instantiating network-based neurodegeneration via mechanisms under ongoing investigation.

The authors report no financial relationships with commercial interests.

Supported by NIH grants K08 AG065502 (to Dr. Miller) and T32 HL007627 (to Dr. Miller).

The authors have confirmed that details of the case have been disguised to protect patient privacy.

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  • Jeffrey Maneval , M.D. ,
  • Kirk R. Daffner , M.D. ,
  • Scott M. McGinnis , M.D.
  • Seth A. Gale , M.A., M.D. ,
  • C. Alan Anderson , M.D. ,
  • David B. Arciniegas , M.D.

a case study of alzheimer disease

  • Posterior Cortical Atrophy
  • Corticobasal Syndrome
  • Atypical Alzheimer Disease
  • Network Degeneration

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Case study unlocks clues to rare resilience to Alzheimer’s disease

Aging Biology Alzheimer's Disease Clinical Research

From NIH Director’s Blog

Biomedical breakthroughs most often involve slow and steady research in studies involving large numbers of people. But sometimes careful study of even just one truly remarkable person can lead the way to fascinating discoveries with far-reaching implications.

Illustration of gold shield on brain

An NIH-funded case study published recently in the journal  Nature Medicine  falls into this far-reaching category [1]. The report highlights the world’s second person known to have an extreme resilience to a rare genetic form of early onset Alzheimer’s disease. These latest findings in a single man follow a 2019 report of a woman with similar resilience to developing symptoms of Alzheimer’s, despite having the same strong genetic predisposition for the disease [2].

The new findings raise important new ideas about the series of steps that may lead to Alzheimer’s and its dementia. They’re also pointing the way to key parts of the brain for cognitive resilience — and potentially new treatment targets — that may one day help to delay or even stop progression of Alzheimer’s.

The man in question is a member of a well-studied extended family from the country of Colombia. This group of related individuals, or kindred, is the largest in the world with a genetic variant called the “Paisa” mutation (or  Presenilin-1 E280A ). This Paisa variant follows an autosomal dominant pattern of inheritance, meaning that those with a single altered copy of the rare variant passed down from one parent usually develop mild cognitive impairment around the age of 44. They typically advance to full-blown dementia around the age of 50 and rarely live past the age of 60. This contrasts with the  most common form of Alzheimer’s , which usually begins after age 65.

The new findings come from a team led by  Yakeel Quiroz , Massachusetts General Hospital, Boston; Joseph Arboleda-Velasquez, Massachusetts Eye and Ear, Boston; Diego Sepulveda-Falla, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; and Francisco Lopera, University of Antioquia, Medellín, Colombia. Lopera  first identified this family  more than 30 years ago and has been studying them ever since.

In the new case report, the researchers identified a Colombian man who’d been married with two children and retired from his job as a mechanic in his early 60s. Despite carrying the Paisa mutation, his first cognitive assessment at age 67 showed he was cognitively intact, having limited difficulties with verbal learning skills or language. It wasn’t until he turned 70 that he was diagnosed with mild cognitive impairment — more than 20 years later than the expected age for this family — showing some decline in short-term memory and verbal fluency.

At age 73, he enrolled in the  Colombia-Boston biomarker research study (COLBOS ). This study is a collaborative project between the University of Antioquia and Massachusetts General Hospital involving approximately 6,000 individuals from the Paisa kindred. About 1,500 of those in the study carry the mutation that sets them up for early Alzheimer’s. As a member of the COLBOS study, the man underwent thorough neuroimaging tests to look for amyloid plaques and tau tangles, both of which are hallmarks of Alzheimer’s.

While this man died at age 74 with Alzheimer’s, the big question is: How did he stave off dementia for so long despite his poor genetic odds? The COLBOS study earlier identified a woman with a similar resilience to Alzheimer’s, which they traced to two copies of a rare, protective genetic variant called Christchurch. This variant affects a gene called apolipoprotein E ( APOE3 ), which is well known for its influence on Alzheimer’s risk. However, the man didn’t carry this same protective variant.

The researchers still thought they’d find an answer in his genome and kept looking. While they found several variants of possible interest, they zeroed in on a single gene variant that they’ve named  Reelin-COLBOS . What helped them to narrow their search down to this variant is the man also had a sister with the Paisa mutation who only progressed to advanced dementia at age 72. It turned out, in addition to the Paisa variant, the siblings also shared an altered copy of the newly discovered  Reelin-COLBOS  variant.

This  Reelin-COLBOS  gene is known to encode a protein that controls signals to chemically modify  tau proteins , which form tangles that build up over time in the Alzheimer’s brain and have been linked to memory loss.  Reelin  is also functionally related to  APOE , the gene that was altered in the woman with extreme Alzheimer’s protection.  Reelin  and  APOE  both interact with common protein receptors in neurons. Together, the findings add to evidence that signaling pathways influencing tau play an important role in Alzheimer’s pathology and protection.

The neuroimaging exams conducted when the man was age 73 have offered further intriguing clues. They showed that his brain had extensive amyloid plaques. He also had tau tangles in some parts of his brain. But one brain region, called the entorhinal cortex, was notable for having a very minimal amount of those hallmark tau tangles.

The entorhinal cortex is a hub for memory, navigation, and the perception of time. Its degeneration also leads to cognitive impairment and dementia. Studies of the newly identified  Reelin-COLBOS  variant in Alzheimer’s mouse models also help to confirm that the variant offers its protection by diminishing the pathological modifications of tau.

Overall, the findings in this one individual and his sister highlight the Reelin pathway and brain region as promising targets for future study and development of Alzheimer’s treatments. Quiroz and her colleagues report that they are actively exploring treatment approaches inspired by the Christchurch and  Reelin-COLBOS  discoveries.

Of course, there’s surely more to discover from continued study of these few individuals and others like them. Other as yet undescribed genetic and environmental factors are likely at play. But the current findings certainly offer some encouraging news for those at risk for Alzheimer’s — and a reminder of how much can be learned from careful study of remarkable individuals.

References:

[1] Lopera F, et al.  Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man . Nat Med. 2023. Epub May 15. doi: 10.1038/s41591-023-02318-3.

[2] Arboleda-Velasquez JF, et. al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: A case report . Nat Med. 2019. Epub Nov. 4. doi: 10.1038/s41591-019-0611-3.

NIH Support: National Institute on Aging; National Eye Institute; National Institute of Neurological Disorders and Stroke; Office of the Director

This research was supported in part by NIA grant R01AG054671.

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  • Case of early-onset Alzheimer’s disease with atypical manifestation
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  • http://orcid.org/0000-0003-1224-4320 Lin Zhu 1 ,
  • Limin Sun 2 ,
  • Lin Sun 3 , 4 and
  • Shifu Xiao 3 , 4
  • 1 Department of Rehabilitation Medicine , Shanghai No.3 Rehabilitation Hospital , Shanghai , China
  • 2 Department of Rehabilitation Medicine , Huashan Hospital Fudan University , Shanghai , China
  • 3 Department of Geriatric Psychiatry , Shanghai Mental Health Center , Shanghai , China
  • 4 Alzheimer's Disease and Related Disorders Center, Shanghai Jiao Tong University , Shanghai , China
  • Correspondence to Professor Shifu Xiao; xiaoshifu{at}msn.com

Short-term memory decline is the typical clinical manifestation of Alzheimer’s disease (AD). However, early-onset AD usually has atypical symptoms and may get misdiagnosed. In the present case study, we reported a patient who experienced symptoms of memory loss with progressive non-fluent aphasia accompanied by gradual social withdrawal. He did not meet the diagnostic criteria of AD based on the clinical manifestation and brain MRI. However, his cerebrospinal fluid examination showed a decreased level of beta-amyloid 42, and increased total tau and phosphorylated tau. Massive amyloid β-protein deposition by 11C-Pittsburgh positron emission tomography confirmed the diagnosis of frontal variant AD. This case indicated that early-onset AD may have progressive non-fluent aphasia as the core manifestation. The combination of individual and precision diagnosis would be beneficial for similar cases.

  • dual (psychiatry)
  • cognition disorders

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ .

https://doi.org/10.1136/gpsych-2020-100283

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Introduction

Clinical report and methods.

Early-onset Alzheimer’s disease (EOAD), which comprises 5% of Alzheimer’s disease (AD), shows a 1.6-year average delay in diagnosis compared with late-onset AD. 1 2 The clinical phenotype of atypical EOAD is heterogeneous, and primary progressive aphasia (PPA) is rarely the initial manifestation of related dementia syndromes. Compared with the progressive non-fluent aphasia (PNFA) related to the language variant phenotype of frontotemporal lobar degeneration (FTLD), molecular imaging studies in patients with primary progressive aphasia suggest the pathological basis of AD. 3 Neurodegeneration uaually starts in a specific neural anatomic networks. The clinical phenotype of PPA can usually infer the type of protein degeneration, which can be used to infer gene mutation. With the development of biomarkers such as genetics, molecular biology, neuroimaging and positron emission tomography (PET), accurate diagnosis can be gradually achieved. In this case study, we describe an AD patient with PNFA as the first symptom.

The patient was a 63-year-old married man, a right-handed businessman, native of Shanghai, with 12 years of school education. He has memory loss and non-fluent speech for 7 years combined with personality changes for 5 years. The patient recovered from hepatitis A 32 years ago and has well-controlled hypertension for 30 years.

The patient’s caregiver described that the patient showed forgetfulness and developed poor pronunciation at the age of 56. His short-term memory has gradually declined as noticed that he repeatedly gave money to customers while selling clothes. He frequently forgot where he parked his bicycle, and it was hard for him to speak a full sentence; his language was vague and short. He was impatient when being asked to repeat a word. Over time, he could only say some single syllables. He evolved into fully aphasia gradually, and his personality also changed gradually. At the age of 59, he could not recognise himself in the mirror and he often hid his shoes because he was worried that they would be stolen. Therefore, his wife had accompanied him to see a neurologist. The physical and neurological examination revealed no remarkable signs. His brain MRI showed mild atrophy in the bilateral frontal lobe ( figure 1A at the age of 59). Fluorodeoxyglucose positron emission tomography (FDG-PET) revealed that glucose metabolism in the bilateral frontal and parietal lobe was declined, and the left side was significant ( figure 1B at the age of 59). The Mini-Mental State Examination (MMSE) score was 18 out of 30 (18/30). At that point, he was diagnosed with cognitive impairment and treated with rivastigmine. After the treatment, his memory improved slightly. In 2017, the neurologist gave him quetiapine and donepezil due to developing visual hallucinations and irritability. The second brain MRI scan revealed increased frontal and temporal atrophy compared with the first one ( figure 1C at the age of 61). The FDG-PET revealed that the cerebral cortical glucose metabolism was further reduced, especially the bilateral frontal and parietal lobes were obvious ( figure 1D at the age of 61).

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Brain imaging and cognitive score of the patient. (A) The patient’s MRI in May 2015 revealed mild atrophy of the bilateral frontal lobe (at the age of 59). (B) The patient’s FDG-PET in May 2015 revealed that glucose metabolism in the bilateral frontal and parietal lobe was reduced, and the left side was significant (at the age of 59). (C) The patient’s MRI in July 2017 (2 years after the first scan), revealed more atrophy of the bilateral frontal lobe and temporal lobe atrophy occurred (at the age of 61). (D) The patient’s FDG-PET in August 2017 revealed that the cerebral cortical glucose metabolism was reduced more, bilateral frontal and parietal lobes obvious in particular (at the age of 61). (E) The patient’s third MRI in May 2019 (2 years after the second scan) revealed atrophy of the whole cerebral cortex with bilateral frontal lobes, temporal lobe and hippocampus more affected (at the age of 63). (F) The patient’s 11C-PIB PET in May 2019 revealed saliently amyloid deposition in diffuse cortical areas, particularly in the bilateral frontal, parietal, temporal cortices and posterior cingulated gyrus (at the age of 63). (G) Mini-Mental State Examination (MMSE) of the patient. MMSE in May 2015 revealed a total score was 18/30 (at the age of 59). MMSE in May and December 2019 revealed a total score were 3/30 and 2/30; the results showed severe impairments in language and other cognitive areas (at the age of 63). 11C-PIB PET, 11C-Pittsburgh compound B positron emission tomography; FDG-PET, fluorodeoxyglucose positron emission tomography.

In May 2019, the patient’s symptoms aggravated further, which included bad temper, crying often and being more difficult to be looked after. His wife brought him to seek help from a psychiatrist, and he was admitted into the Department of Geriatric Psychiatry of Shanghai Mental Health Center. He underwent routine laboratory tests to exclude non-neurodegenerative and dementia. His neurological examination showed gait abnormality, negative Babinski’s sign, muscular tension hyperactivity, knee jerk reflex hyperactivity and a weak positive right palmar jaw reflex. The MMSE score was 3/30. The patient exhibited severe impairments in orientation (2/10), attention and calculation (1/5), recall (0/6), language (0/8) and visual construction (0/1). The Montreal Cognitive Assessment score was 0 (0/30), which was significantly lower than it was in 2015( figure 1G ). The third brain MRI demonstrated atrophy of the cerebral cortex, especially in the bilateral frontal lobes and hippocampus. The medial temporal lobe atrophy scale was at grade 3 ( figure 1E at the age of 63).

In addition, we tested three pathogenic genes for early-onset AD including amyloid precursor protein, presenilin-1, presenilin-2 genes related to neurocognitive disorders, but no mutation was found. Apolipoprotein E (APOE) genotyping showed APOE ε3/ε3 type. In order to reach a definite diagnosis, the patient underwent 11C-Pittsburgh compound B positron emission tomography (11C-PIB PET) and cerebrospinal fluid (CSF) examination. 11C-PIB PET revealed noticeable amyloid deposition in diffuse cortical areas, particularly in the bilateral frontal, parietal, temporal cortices and posterior cingulated gyrus ( figure 1F at the age of 63). The measured CSF biomarkers showed decreased amyloid β-protein (Aβ) 42 (462 pg/ml; cut-off >562 pg/ml), increased total tau (754 pg/ml; cut-off <370 pg/ml) and increased phosphorylated tau (87.40 pg/ml; cut-off <66.26 pg/ml). Eventually, the diagnosis of frontal variant EOAD was reconfirmed considering the early onset of dementia, the slow progression of symptoms, the absence of focal neurological damage signs and the exclusion of other systemic or brain diseases that could cause dementia. Due to the gastrointestinal adverse reactions of the patient, rivastigmine was suspended. We used memantine 10 mg b.i.d. and donepezil 5 mg q.d. to improve cognition and to control psychobehavioural symptoms and vortioxetine 10 mg q.d. to improve mood. After the treatment and follow-up for 7 months, the patient’s behaviour and mood was improvved significally, and his language expression improved slightly ( figure 1G at the age of 63).

The initial clinical manifestations of the patient included short-term memory decline, poor pronunciation and personality changes at an early stage, followed by behavioural and psychological symptoms of dementia, including hallucinations, delusions of theft, gradual decline in self-care as well as depression. The patient’s brain MRI initially showed mild atrophy of the bilateral frontal lobe. With the progress of the disease, more severe atrophy of the cerebral cortex, temporal lobe and hippocampus appeared besides the further atrophy of the bilateral frontal lobe. The atypical manifestation such as early aphasia, frontal lobe atrophy and personality changes can mislead clinicians in diagnosing frontotemporal lobar degeneration. This is the main reason leading to the misdiagnosis of this patient, which should be taken as a lesson or future reference for clinicians.

According to the current classification schemes, the clinical symptoms were in line with PNFA, which are halting speech by speech sound errors with spared content word comprehension and atrophy of the left frontal lobe. 4 PNFA is one of the primary progressive aphasias. 4 This patient met the diagnostic criteria of frontotemporal dementia, consistent with the early personality changes and cognitive abnormalities. 5 In the past 7 years, the patient’s speech fluency and cognitive function decreased continuously and rapidly. The clinical manifestations could not be explained by typical AD. The CSF phosphorylated tau was slightly higher, and no gene mutations associated with AD were found, which further made it harder to reach the diagnosis. However, the 11C-PIB PET showed heavy and extensive Aβ-amyloid depositions and provided definite pathological evidence of AD. A retrospective study found PNFA with 13%– 31% of cases might have the pathology of AD. 6 The patient met the research diagnostic AT(N) framework of AD, with A: (11C-PIB PET revealed amyloid depositions, CSF Aβ42 decreased), T: (CSF phosphorylated microtubule-associated protein tau increased) and N: (cortical atrophy on MRI, glucose hypometabolism in the bilateral frontal parietal lobe and CSF total microtubule-associated protein tau increased). 7 We use the AD pathological markers as the gold standard to exclude other types of dementia and reach an earlier and more accurate diagnosis. It’s worth pointing out that the patient might have mixed neuropathology. Santos-Santos 6 found that 75% of PNFA or PPA cases may have mixed pathological changes of FTLD and AD. This poses a new challenge for clinicians, suggesting that verified, reliable and accessible biomarkers for diagnosis of FTLD should be developed urgently. Otherwise, the comorbid pathological cases would only be accurately diagnosed after autopsy.

After reaching a clear diagnosis, and according to the China guidelines for the diagnosis and treatment of dementia and cognitive impairment in 2018 and the guidelines for the diagnosis and treatment of AD, 8 the patient was treated with cholinesterase inhibitors and excitatory amino acid receptor antagonists to enhance cognition, and antidepressants were given to relieve his mood. After the treatment, the patient’s symptoms were improved, and his mood was stable. Additionally, the biopsychosocial medical model has become more and more accepted. We should treat the patients with medication and non-drug intervention for patients and their caregivers. Spouses and caregivers of patients with early-onset dementia bear a greater burden and higher depression rates. 9 The speech impairments of this patient appeared early. He was emotionally unstable, grumpy and easy to be tearful, which was alleviated when his wife comforted him. Two weeks later, he was released from the hospital and continued to receive comprehensive rehabilitation treatments. Anyway, providing individualised psychosocial support for patients and their caregivers is very important for improving symptoms and quality of life. 10

Some of PNFAs are due to the underlying pathology of AD, which is more common in EOAD. In the present case, neither clinical examination nor MRI could definitively differentiate FTLD from EOAD. According to AT(N) research framework, we could eventually confirm the neuropathy diagnosis of AD or frontal-variant AD (fvAD), but the previous misdiagnoses were significant. FvAD can lead to social withdrawal and depression. These patients should benefit from accurate diagnosis, medication treatment and individualised psychosocial intervention.

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Lin Zhu obtained a bachelor’s degree in clinical medicine from Shanghai Jiao Tong University School of Medicine, Shanghai, China in 2006. She is currently working as an attending doctor and psychotherapist at the Neurorehabilitation Department of Shanghai Third Rehabilitation Hospital. After completing clinical training, she started a two-year master program and was certified by the Institute of Psychology of the Chinese Academy of Sciences. In addition, she has also been trained and actively involved in clinical neurological research for half year in the Department of Geriatric Psychiatry of Shanghai Mental Health Center, Shanghai, China. Her main research interest includes the rehabilitation of elderly with psychiatric disorders.

Contributors LZ drafted the case report and manuscript; LMS performed the literature search; LS and SX supervised and revised the manuscript. All authors approved the final manuscript.

Funding This study was supported by a grant of Clinical Research Centre Project of Shanghai Mental Health Centre (CRC2017ZD02) and Scientific Research Program of Shanghai Jing an District Health Committee (2020MS16).

Competing interests None declared.

Patient consent for publication Parental/guardian consent obtained.

Provenance and peer review Not commissioned; externally peer reviewed.

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Comprehensive Review on Alzheimer’s Disease: Causes and Treatment

Alzheimer’s disease (AD) is a disorder that causes degeneration of the cells in the brain and it is the main cause of dementia, which is characterized by a decline in thinking and independence in personal daily activities. AD is considered a multifactorial disease: two main hypotheses were proposed as a cause for AD, cholinergic and amyloid hypotheses. Additionally, several risk factors such as increasing age, genetic factors, head injuries, vascular diseases, infections, and environmental factors play a role in the disease. Currently, there are only two classes of approved drugs to treat AD, including inhibitors to cholinesterase enzyme and antagonists to N -methyl d -aspartate (NMDA), which are effective only in treating the symptoms of AD, but do not cure or prevent the disease. Nowadays, the research is focusing on understanding AD pathology by targeting several mechanisms, such as abnormal tau protein metabolism, β-amyloid, inflammatory response, and cholinergic and free radical damage, aiming to develop successful treatments that are capable of stopping or modifying the course of AD. This review discusses currently available drugs and future theories for the development of new therapies for AD, such as disease-modifying therapeutics (DMT), chaperones, and natural compounds.

1. Introduction

Alzheimer’s disease (AD) (named after the German psychiatric Alois Alzheimer) is the most common type of dementia and can be defined as a slowly progressive neurodegenerative disease characterized by neuritic plaques and neurofibrillary tangles ( Figure 1 ) as a result of amyloid-beta peptide’s (Aβ) accumulation in the most affected area of the brain, the medial temporal lobe and neocortical structures [ 1 ]. Alois Alzheimer noticed a presence of amyloid plaques and a massive loss of neurons while examining the brain of his first patient that suffered from memory loss and change of personality before dying and described the condition as a serious disease of the cerebral cortex. Emil Kraepelin named this medical condition Alzheimer’s disease for the first time in his 8th edition psychiatry handbook [ 2 , 3 ]. Progressive loss of cognitive functions can be caused by cerebral disorder like Alzheimer’s disease (AD) or other factors such as intoxications, infections, abnormality in the pulmonary and circulatory systems, which causes a reduction in the oxygen supply to the brain, nutritional deficiency, vitamin B12 deficiency, tumors, and others [ 4 , 5 ].

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Object name is molecules-25-05789-g001.jpg

The physiological structure of the brain and neurons in ( a ) healthy brain and ( b ) Alzheimer’s disease (AD) brain.

At present, there are around 50 million AD patients worldwide and this number is projected to double every 5 years and will increase to reach 152 million by 2050. AD burden affects individuals, their families, and the economy, with estimated global costs of US$1 trillion annually. At present, there is no cure for Alzheimer’s disease, although there are available treatments that just improve the symptoms [ 6 , 7 ]. The purpose of this review is to give a brief description about AD diagnosis, pathology, causes, and current treatments, and to highlight the recent development of compounds that could prevent or treat AD by targeting several pathogenic mechanisms, such as Aβ and tau aggregation, and misfolding, inflammation, oxidative damage, and others.

2. Alzheimer’s Disease Diagnostic Criteria

A patient suspected to have AD should undergo several tests, including neurological examination, magnetic resonance imaging (MRI) for neurons, laboratory examinations such as vitamin B12, and other tests besides the medical and family history of the patients [ 8 ]. Vitamin (vit.) B12 deficiency has been long known for its association with neurologic problems and increasing risks of AD, according to some studies. A special marker of vit. B12 deficiency is elevated homocysteine levels, which can cause brain damage by oxidative stress, increasing calcium influx and apoptosis. Diagnoses of vit. B12 deficiency can be done by measuring serum vit. B12 level alongside complete blood count and serum homocysteine levels tests [ 9 , 10 ].

In 1984, The National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer’s Disease and Related Disorders Association (ADRDA) formed a work group (NINCDS-ADRDA) to establish a clinical diagnostic’s criteria for Alzheimer’s disease. This criteria includes: (1) probable Alzheimer’s disease, which can be diagnosed by dementia that is confirmed by neuropsychological tests, progressive memory loss, impaired daily-life activity, and other symptoms like aphasia (impairment of a language), apraxia (a motor skills disorder), and agnosia (a loss of perception). All of these symptoms can start from age 40–90, with the absence of any systemic or brain diseases, (2) possible Alzheimer’s disease can be applied in the absence of neurologic, psychiatric disorders, and the presence of another illness like systemic or brain disorder, but they are not the primary cause of dementia, and (3) definite Alzheimer’s disease, that is confirmed by histopathologic confirmation obtained from a biopsy or autopsy [ 11 , 12 ].

In 2011, The National Institute on Aging—Alzheimer’s Association made several changes and updated the 1984 NINCDS-ADRDA criteria for higher specificity and sensitivity in the diagnosis of Alzheimer’s disease. The newly proposed criteria include probable and possible AD dementia for the use in clinical settings and probable or possible AD dementia with pathophysiological evidence for research purposes, in addition to clinical biomarkers. There are two categories of Alzheimer’s disease biomarkers: (a) markers of brain amyloid such as positron emission tomography (PET) and cerebrospinal fluid (CSF), and (b) markers of neuronal injury like cerebrospinal fluid tau, fluorodeoxyglucose (FDG) for metabolic activity, and magnetic resonance imaging (MRI) for atrophy measurement [ 13 , 14 , 15 ].

3. Alzheimer’s Disease’s Neuropathology

There are two types of neuropathological changes in AD which provide evidence about disease progress and symptoms and include: (1) positive lesions (due to accumulation), which are characterized by the accumulation of neurofibrillary tangles, amyloid plaques, dystrophic neurites, neuropil threads, and other deposits found in the brains of AD patients. In addition to (2) negative lesions (due to losses), that are characterized by large atrophy due to a neural, neuropil, and synaptic loss. Besides, other factors can cause neurodegeneration such as neuroinflammation, oxidative stress, and injury of cholinergic neurons [ 16 , 17 , 18 ].

3.1. Senile Plaques (SP)

The senile plaques are extracellular deposits of beta-amyloid protein (Aβ) with different morphological forms, including neuritic, diffuse, dense-cored, or classic and compact type plaques. Proteolytic cleavage enzymes such as β-secretase and γ-secretase are responsible for the biosynthesis of Aβ deposits from the transmembrane amyloid precursor protein (APP) [ 19 , 20 , 21 ]. These enzymes cleave APP into several amino acid fragments: 43, 45, 46, 48, 49, and 51 amino acids, which reach the final forms Aβ40 and Aβ42. There are several types of Aβ monomers, including large and insoluble amyloid fibrils which can accumulate to form amyloid plaques and soluble oligomers that can spread throughout the brain. Aβ plays a major role in neurotoxicity and neural function, therefore, accumulation of denser plaques in the hippocampus, amygdala, and cerebral cortex can cause stimulation of astrocytes and microglia, damage to axons, dendrites, and loss of synapses, in addition to cognitive impairments [ 21 , 22 , 23 ].

3.2. Neurofibrillary Tangles (NFTs)

NFT are abnormal filaments of the hyperphosphorylated tau protein that in some stages can be twisted around each other to form paired helical filament (PHF) and accumulate in neuralperikaryal cytoplasm, axons, and dendrites, which cause a loss of cytoskeletal microtubules and tubulin-associated proteins. The hyperphosphorylated tau protein is the major constituent of NFTs in the brains of AD patients, and its evolution can reflect NFTs morphological stages, which include: (1) pre-tangle phase, one type of NFT, where phosphorylated tau proteins are accumulated in the somatodendritic compartment without the formation of PHF, (2) mature NFTs, which are characterized by filament aggregation of tau protein with the displacement of the nucleus to the periphery part of the soma, and (3) the extracellular tangles, or the ghost NFTs stage, that results from a neuronal loss due to large amounts of filamentous tau protein with partial resistance to proteolysis [ 24 , 25 ].

3.3. Synaptic Loss

A synaptic damage in the neocortex and limbic system causes memory impairment and generally is observed at the early stages of AD. Synaptic loss mechanisms involve defects in axonal transport, mitochondrial damage, oxidative stress, and other processes that can contribute to small fractions, like the accumulation of Aβ and tau at the synaptic sites. These processes eventually lead to a loss of dendritic spines, pre-synaptic terminals, and axonal dystrophy [ 26 ]. Synaptic proteins serve as biomarkers for the detection of synapses loss, and severity, such as neurogranin, a postsynaptic neuronal protein, visinin-like protein-1 (VILIP-1), and synaptotagmin-1 [ 27 , 28 ].

4. The Stages of Alzheimer’s Disease

The clinical phases of Alzheimer’s disease can be classified into (1) pre-clinical or the pre-symptomatic stage, which can last for several years or more. This stage is characterized by mild memory loss and early pathological changes in cortex and hippocampus, with no functional impairment in the daily activities and absence of clinical signs and symptoms of AD [ 1 , 29 , 30 ]. (2) The mild or early stage of AD, where several symptoms start to appear in patients, such as a trouble in the daily life of the patient with a loss of concentration and memory, disorientation of place and time, a change in the mood, and a development of depression [ 30 , 31 ]. (3) Moderate AD stage, in which the disease spreads to cerebral cortex areas that results in an increased memory loss with trouble recognizing family and friends, a loss of impulse control, and difficulty in reading, writing, and speaking [ 30 ]. (4) Severe AD or late-stage, which involves the spread of the disease to the entire cortex area with a severe accumulation of neuritic plaques and neurofibrillary tangles, resulting in a progressive functional and cognitive impairment where the patients cannot recognize their family at all and may become bedridden with difficulties in swallowing and urination, and eventually leading to the patient’s death due to these complications [ 1 , 32 ].

5. Causes and Risk Factors of Alzheimer’s Disease

AD has been considered a multifactorial disease associated with several risk factors ( Figure 2 ) such as increasing age, genetic factors, head injuries, vascular diseases, infections, and environmental factors (heavy metals, trace metals, and others). The underlying cause of pathological changes in Alzheimer’s disease (Aβ, NFTs, and synaptic loss) is still unknown. Several hypotheses were proposed as a cause for AD but two of them are believed to be the main cause: some believe that an impairment in the cholinergic function is a critical risk factor for AD, while others suggest that alteration in amyloid β-protein production and processing is the main initiating factor. However, at present, there is no accepted theory for explaining the AD pathogenesis [ 33 , 34 ].

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The risk factors for Alzheimer’s disease.

5.1. Alzheimer’s Disease Hypotheses

5.1.1. cholinergic hypothesis.

In the 1970s, neocortical and presynaptic cholinergic deficits were reported to be related to the enzyme choline acetyltransferase (ChAT), which is responsible for the synthesis of acetylcholine (ACh). Due to the essential role of ACh in cognitive function, a cholinergic hypothesis of AD was proposed. ACh is synthesized in the cytoplasm of cholinergic neurons from choline and acetyl-coenzyme A by the ChAT enzyme and transported to the synaptic vesicles by vesicular acetylcholine transporter (VAChT) ( Figure 3 ). In the brain, ACh is involved in several physiological processes such as memory, attention, sensory information, learning, and other critical functions. Degeneration of the cholinergic neurons was found to take place in AD and to cause alternation in cognitive function and memory loss. Β -amyloid is believed to affect cholinergic neurotransmission and to cause a reduction in the choline uptake and a release of ACh. Studies demonstrated that cholinergic synaptic loss and amyloid fibril formation are related to Aβ oligomers’ neurotoxicity and to interactions between AChE and Aβ peptide. Additional factors also contribute to the progression of AD, such as a reduction in nicotinic and muscarinic (M2) Ach receptors, located on presynaptic cholinergic terminals, and the deficit in excitatory amino acid (EAA) neurotransmission, where glutamate concentration and D-aspartate uptake are significantly reduced in many cortical areas in AD brains. This is in addition to the use of cholinergic receptor antagonists such as scopolamine, which was found to induce amnesia. This effect can be reversed by using compounds that activate acetylcholine formation [ 35 , 36 , 37 ].

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The pathway for the synthesis and transportation of acetylcholine between presynaptic and postsynaptic nerve terminals.

As a result, the cholinergic hypothesis is based on three concepts: reduced presynaptic cholinergic markers in the cerebral cortex, severe neurodegeneration of nucleus basalis of Meynert (NBM) in the basal forebrain, which is the source of cortical cholinergic innervation, and the role of cholinergic antagonists in memory decline compared to the agonists, which have the opposite effect [ 38 ].

5.1.2. Amyloid Hypothesis

For decades, it was recognized that abnormal deposition of β-sheets in the central nervous system has a strong correlation with dementia, which led to the concept of the amyloid hypothesis. However, it was found that the amyloid plaques (AP) also deposit in normal healthy brains with aging, which raised the question of whether AP deposition is responsible for AD onset or not? Therefore, in the recent years, alternative hypotheses were proposed for the non-inherited form of AD (NIAD), but at present, the amyloid hypothesis remains the most accepted pathological mechanism for inherited AD (IAD). The amyloid hypothesis suggests that the degradation of Aβ, derived from APP by β- and γ-secretase, is decreased by age or pathological conditions, which leads to the accumulation of Aβ peptides (Aβ40 and Aβ42). Increasing the ratio of Aβ42/Aβ40 induces Aβ amyloid fibril formation, resulting in neurotoxicity and tau pathology induction, and consequently, leading to neuronal cell death and neurodegeneration. AD risk factors and mutations of several genes like APP, PSEN1, and PSEN2 were found to affect Aβ catabolism and anabolism, which rapidly cause an accumulation of Aβ and fast progression of neurodegeneration [ 39 , 40 , 41 ].

5.2. Alzheimer’s Disease Risk Factors

5.2.1. aging.

The most important risk factor in AD is aging. Younger individuals rarely have this disease, and most AD cases have a late onset that starts after 65 years of age [ 42 ]. Aging is a complex and irreversible process that occurs through multiple organs and cell systems with a reduction in the brain volume and weight, a loss of synapses, and ventricles’ enlargement in specific areas accompanied by SP deposition and NFT. Moreover, several conditions might emerge during aging such as glucose hypometabolism, cholesterol dyshomeostasis, mitochondria dysfunction, depression, and cognitive decline. These changes also appear in normal aging, which makes it difficult to distinguish the cases in early AD [ 43 , 44 ]. AD can be divided based on age of onset into early-onset AD (EOAD), the rare form with around 1–6% of cases, in which most of them are familial AD characterized by having more than one member in more than one generation with AD, and ranges from 30–60 or 65 years. The second type is the late-onset AD (LOAD), which is more common with age of onset above 65 years. Both types may occur in people who have a family with a positive history of AD and families with a late-onset disease [ 45 ].

5.2.2. Genetics

Genetic factors were discovered over the years and were found to play a major role in the development of AD. 70% of the AD cases were related to genetic factors: most cases of EOAD are inherited in an autosomal dominant pattern and mutations in the dominant genes such as Amyloid precursor protein (APP) , Presenilin-1 (PSEN-1), Presenilin-2 (PSEN-2) , and apolipoprotein E (ApoE) are associated with AD [ 46 , 47 ].

Herein, we discuss the strong genetic risk factors in AD.

  • Amyloid Precursor Protein (APP)

APP is a type I transmembrane protein cleaved by α-, β-, and γ-secretase to release Aβ and other proteins and is encoded by the APP gene on chromosome 21. Thirty mutations have been found in the APP gene in which twenty-five of them are related to AD and cause an accumulation of Aβ with elevated amounts. Meanwhile, there is one protective mutation, A673T, which protects against AD by decreasing Aβ, Aβ40, and Aβ42 secretion [ 48 , 49 ]. All mutations surround the secretase cleavage site, for example, the KM670/671NL mutation in mouse models has shown an increasing level of amyloid plaques in the hippocampus and cortex with no NFTs. A673V, D678H, D678N, E682K, and K687N mutations have shown cortical atrophy, whereas E682K has shown hippocampal atrophy. Neuropathological reports for the A673V mutation demonstrated a presence of NFTs and Aβ, activation of microglia and astrocytes, and neuronal loss, compared to the rest of the mentioned mutations, which show no change in the intracellular Aβ according to neuropathological reports [ 48 , 50 ]. Other mutations such as T714I, V715A, V715M, V717I, V717L, L723P, K724N, and I716V affect the γ-secretase cleavage site and cause an increase in the Aβ42/Aβ40 ratio, while E693G, E693K, D694N, and A692G mutations affect the α-secretase cleavage site and cause polymorphic aggregates with the ability to disrupt bilayer integrity. Also, the E693delta is a deletion mutation that enhances the formation of synaptotoxic Aβ [ 51 , 52 ].

  • Presenilin-1 (PSEN-1) and Presenilin-2 (PSEN-2)

PSEN1 and PSEN2 genes are also the autosomal dominant form of EOAD located on chromosomes 14 and 1, respectively. PSEN-2 and PSEN-1 are homologous, with 67% similarity, with a difference in the N -terminus and the hydrophilic region. Mutation in PSEN1 gene is more common, with more than 200 mutations, while a rare form with less than 40 mutations was identified in the PSEN2 gene [ 53 , 54 ].

PSEN1 is a core protein that activates the γ-secretase complex and plays an important role in the production of Aβ from APP. Knockout studies of PSEN1 showed synaptic dysfunction and memory impairment in mice, which indicate its essential role in maintaining memory and neurons [ 51 ]. PSEN1 mutations are simple ones which include single amino acid substitution, and severe mutation can result from the substitutions of two amino acids [ 55 ]. Mutations in the PSEN1 gene increase the ratio of Aβ42/Aβ40 by decreasing Aβ40 levels. The results obtained by Sun et al. study demonstrated that C410Y or L435F mutations in PSEN1 knock-in mice increased the Aβ42/Aβ40 ratio due to a greater reduction in Aβ40 [ 56 ].

In contrast, PSEN-2 mutations are rare and play a minor role in Aβ production. Any mutation in PSEN-2 might have a severe effect on the Aβ 42/40 ratio, causing familial AD in the presence of normal PSEN-1 alleles. Some of the PSEN-2 mutations cause a significant increase in γ-secretase activity with an elevation in the Aβ-42 and Aβ 42/40 ratio level, such as N141I, T122P, M239V, and M239I, while others are rare polymorphisms and have no effect on Aβ-42, -40, and Aβ 42/40 ratio levels and are not considered as pathogenic mutations [ 53 , 57 ].

  • Apolipoprotein E (ApoE)

ApoE protein is a glycoprotein expressed highly in the liver and brain astrocytes and some microglia and serves as a receptor-mediated endocytosis ligand for lipoprotein particles like cholesterol, which is essential for myelin production and normal brain function. The ApoE gene located on chromosome 19 has three isoforms, ApoE2, ApoE3, and ApoE4, due to single-nucleotide polymorphisms (SNPs) which cause changes in the coding sequence. The ApoEε4 allele is a strong risk factor for both EOAD and LOAD compared to ApoEε2 and ApoEε3 alleles that are associated with a lower risk and protective effect, respectively [ 58 ]. ApoEε4 plays an important role in Aβ deposition as a senile plaque and causes cerebral amyloid angiopathy (CAA), which is known as a marker for AD [ 59 ]. ApoEε4 was also shown to be associated with vascular damage in the brain, which leads to AD pathogenesis [ 60 ].

  • ATP Binding Cassette Transporter A1 (ABCA1)

Adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) is part of a large ABC transporters family that regulate cholesterol efflux in the circulation, like apolipoproteins-AI (ApoAI), and into the brain, like ApoE. In addition, ABCA1 maintains the stability of ApoE lipidation and serves as a mediator for high-density lipoprotein (HDL) generation, which reflects its role in atherosclerosis and cardiovascular diseases. Studies on the AD mice model showed that ABCA1 deficiency increases amyloid plaques and eliminates the lipidation of ApoE [ 61 ]. In humans, a mutation in ABCA1 results in Tangier disease, which is characterized by low levels of high-density lipoprotein (HDL) and ApoAI in plasma, accumulation of cholesterol in tissues, and AD pathogenesis [ 62 ].

  • Clusterin Gene (CLU) and Bridging Integrator 1 ( BIN1 )

In contrast to PSEN1 , PSEN2 , and APP mutations, which result in familial or EOAD, clusterin ( CLU) and Bridging Integrator 1 ( BIN1 ) genes are novel risk factors for LOAD. In 2009, Genome-Wide Association Studies (GWAS) identified the CLU gene located on chromosome 8, which is upregulated in the cortex and hippocampus of AD brains, in addition to AD cerebrospinal fluid (CSF) and plasma, which make the CLU a promising biomarker for AD. The CLU may play a protective role by interacting with Aβ and promoting its clearance, or a neurotoxic role by reducing Aβ clearance. The Aβ ratio values determine whether the CLU role is neuroprotective or neurotoxic [ 63 ].

BIN1 is a Bin-Amphiphysin-Rvs (BAR) adaptor protein that is involved in the production of membrane curvature and other endocytosis cellular functions. BIN1 has several isoforms: some are found in the brain, where they interact with different proteins such as clathrin, synaptojanin, and amphiphysin 1, and others in which they regulate synaptic vesicle endocytosis. Recently, BIN1 was recognized as the second most important risk factor for LOAD after ApoE, where it plays a role in Aβ production and as a tau and NFT pathology modulator [ 64 , 65 ].

  • Evolutionarily Conserved Signaling Intermediate in Toll pathway (ECSIT)

A significant accumulation of Aβ in AD brains increases protein oxidation, which reflects the critical role of mitochondria in Aβ cytotoxicity and AD pathogenesis. Evolutionarily conserved signaling intermediate in Toll pathway (ECSIT) gene is located on chromosome 19 and is associated with increasing the risk of AD. ECSIT encodes the adapting protein that functions as a cytoplasmic and signaling protein and is responsible for stabilizing the mitochondrial respiratory complex. Moreover, the adaptor protein is involved in the activation of nuclear factor (NF)-κB, interferon regulatory factors (IRFs), and activating protein-1. Also, it is involved in coupling immune toll-like receptor (TLR), homeostatic bone morphogenetic pathway (BMP), and transforming growth factor-beta (TGF-b) pathways [ 66 , 67 ].

ECSIT interacts with mitochondrial proteins such as Lon protease homolog (LONP1) and glutaryl-CoA dehydrogenase (GCDH), which are involved in intra-mitochondrial proteolysis and redox signaling respectively, followed by interactions with AD seed nitric oxide synthase (NOS3). Moreover, studies have shown certain interactions of ECSIT with the AD genes ApoE , PSEN-1 , and PSEN-2 . These interactions support the role of ECSIT as a molecular link in oxidative stress, inflammation, and mitochondrial dysfunction in AD [ 66 , 68 ].

  • Estrogen Receptor Gene (ESR)

AD affects both women and men, but nearly two-thirds of AD cases are women. Several studies have shown that women with AD experience worse mental deterioration than men. Additionally, on the genetic level, some genes’ variation, like the ApoE4 allele, significantly increases AD risk in women compared to men. Other studies documented that AD risk in women is associated with the loss of ovarian hormones during menopause due to the fact that estrogen regulates several activities in the brain, such as neurotransmission, neural development, survival, protection against oxidative stress, reduction of Aβ peptide levels, and attenuation of tau hyperphosphorylation. The estrogen activity is mediated through estrogen receptors (ERs) (intracellular, transmembrane, and membrane-bound ERs). The two major subtypes of these receptors are ERα and Erβ, which are encoded by two distinct genes and are located on chromosome 6 and 14, respectively. ERα receptor is found in the hypothalamus and amygdala, whereas ERβ receptors are in the hippocampus and cortex. Single nucleotide polymorphisms (SNPs) in ERβ and ERα genes may affect exogenous estrogen in older women and influence cognitive aging. PvuII (rs9340799) and Xbal (rs223493) are examples of SNPs found in ERα and are associated with AD and cognitive impairment. Also, several SNPs in ERβ have been proven to increase the risk of AD in women [ 69 , 70 , 71 , 72 ].

  • Other Genes

Other genes’ polymorphism associated with increasing the risk of AD include vitamin D receptor (VDR) gene polymorphism, which affects the affinity of vitamin D to its receptor and may cause neurodegenerative diseases and neuronal damage [ 73 ]. Moreover, epigenetic factors like DNA methylation, histone, and chromatin modifications were demonstrated to be involved in AD [ 33 , 74 ].

5.2.3. Environmental Factors

Aging and genetic risk factors cannot explain all cases of AD. Environmental risk factors including air pollution, diet, metals, infections, and many others may induce oxidative stress and inflammation and increase the risk for developing AD. Herein, we report the most important environmental factors and their relationships with AD [ 75 , 76 ].

  • Air Pollution

The air pollution is characterized by modifying the nature of the atmosphere through the introduction of chemical, physical, or biological pollutants. It is associated with respiratory and cardiovascular diseases and recently, its association with AD was documented. Six air pollutants have been defined by National Ambient Air Quality Standards (NAAQSs) in the USA as a threat to human health, including ozone (O 3 ), nitrogen oxides (NO x ), carbon monoxide (CO), particulate matter (PM), sulfur dioxide (SO 2 ), and lead. Studies on animals and cellular models have shown that an exposure to high levels of air pollution can result in a damage to the olfactory mucosa and bulb, in addition to the frontal cortex region, similar to that observed in AD. In individuals exposed to air pollutants, there is a link between oxidative stress, neuroinflammation, and neurodegeneration, with the presence of hyper-phosphorylated tau and Aβ plaques in the frontal cortex. The air pollution can cause an increase in Aβ 42 formation, accumulation, and impaired cognitive function [ 77 , 78 ].

In recent years, the number of studies on the role of nutrition in AD have been increased. Several dietary supplements such as antioxidants, vitamins, polyphenols, and fish were reported to decrease the risk of AD, whereas saturated fatty acids and high-calorie intake were associated with increasing the risk of AD [ 79 ]. The food processing causes degradation of heat-sensitive micronutrients (e.g., vitamin C and folates), loss of large amounts of water, and formation of toxic secondary products (advanced glycation end products, AGEs) from non-enzymatic glycation of free amino groups in proteins, lipids, and nucleic acids. The toxic effect of AGEs is referred to as their ability to induce oxidative stress and inflammation by modifying the structure and function of the cell surface receptors and body proteins. Different studies demonstrated that elevated AGEs serum level is associated with cognitive decline and progression of AD. The AGE receptor (RAGE) is located in different places within the body, including microglia and astrocytes, and was established to be overexpressed in the brain of AD patients and serve as a transporter and a cell surface receptor for Aβ [ 80 ]. Malnutrition is another risk factor for AD. Deficiency in nutrients such as folate, vitamin B12, and vitamin D may cause a decrease in cognitive function, in addition to the fact that patients with AD suffer from problems associated with eating and swallowing, which may increase the risk of malnutrition [ 81 ].

Metals are found in nature and biological systems and can be divided into bio-metals that have a physiological function in living organisms (e.g., copper, zinc, and iron), and toxicological metals which do not possess any biological function (e.g., aluminum and lead) [ 82 ]. Aluminum is used significantly in the industries such as processed foods, cosmetics, medical preparations, medicines, and others. In the body, aluminum is bound to plasma transferrin and to citrate molecules that can mediate the transfer of aluminum to the brain. Studies demonstrated that Al accumulates in the cortex, hippocampus, and cerebellum areas, where it interacts with proteins and causes misfolding, aggregation, and phosphorylation of highly phosphorylated proteins like tau protein, characteristic of AD [ 83 ]. Lead competes with the binding site of bio-metals like calcium and can cross the blood–brain barrier (BBB) rapidly, where it can modify neural differentiation and synaptogenesis and cause severe damage. Studies revealed that an acute exposure to lead was associated with AD and caused an increase of β-secretase expression and Aβ accumulation. Cadmium is a carcinogenic water-soluble metal that can cross the BBB and cause neurological diseases like AD. Results have demonstrated that Cadmium ions are involved in the aggregation of Aβ plaques and the self-aggregation of tau in the AD brain. The data accumulated on metals support the notion that they are among the risk factors involved in the development of AD [ 84 ].

Chronic infections to the central nervous system (CNS) can cause an accumulation of Aβ plaques and NFT, therefore, they are included among the risk factors in AD. Studies by Dr. Itzhaki showed that the DNA of herpes simplex virus (HSV-1) was found in patients with ApoE-ε4 allele carriers, which explains the high risk for developing AD. HSV-1 can replicate in the brain, which can result in the activation of the inflammatory response and an increase in Aβ deposition, resulting in damage to neurons and gradual development of AD. On the other hand, the study results by Miklossy and Balin’s have revealed the role of chronic bacterial infections in AD. For example, syphilitic dementia caused by spirochete bacteria ( Treponema pallidum ), which are accumulated in the cerebral cortex, produced lesions similar to neurofibrillary tangles, which led to devastating neurodegenerative disorders. Besides, Chlamydia pneumonia bacterium can trigger late-onset AD by activation of astrocyte and cytotoxic microglia, disrupt calcium regulation and apoptosis, resulting in deterioration of cognitive function, and increase the risk of AD [ 85 , 86 , 87 ].

5.2.4. Medical Factors

Several risk factors are related to the development of Alzheimer’s disease. Adding to this list, older people with AD usually have medical conditions such as cardiovascular disease (CVD), obesity, diabetes, and others. All of these conditions are associated with increased risk of AD [ 88 , 89 ].

  • Cardiovascular Disease (CVDs)

CVDs are recognized as an important risk factor for AD, such as the stroke that is associated with increased risk of dementia due to a neural tissue loss, which enhances degenerative effect and influences amyloid and tau pathology. Atrial fibrillation also causes embolisms which leads to stroke and a decrease in memory and cognitive functions. Moreover, heart failure affects the pumping function of the heart and results in insufficient blood supply to the body and hypo-perfusion of the brain that leads to hypoxia and neural damage. The coronary heart disease’s hypothesis indicates that atherosclerosis, peripheral artery disease, hypo-perfusion, and emboli are all related to increased risk of AD. Hypertension is associated with thickening of vessel walls and narrowing of the lumen which reduce the cerebral blood flow, and in chronic cases, it may cause cerebral edema, which all participate as risk factors for AD and CVD. The CVD is a modifiable risk factor and by focusing on its relationship with AD, a pathway to prevent and delay the disease can be obtained [ 89 , 90 ].

  • Obesity and Diabetes

Obesity is a term used for too much body fat in individuals due to consuming more calories than they burn and can be calculated by using the body mass index (BMI). Increasing the body fat is associated with a decreased brain blood supply which promotes brain ischemia, memory loss, and vascular dementia. The obesity, unhealthy diet, and other factors can cause impaired glucose tolerance (IGT) or diabetes, which is characterized by hyperglycemia that affects peripheral tissues and blood vessels. Chronic hyperglycemia can induce cognitive impairment as a result of increasing amyloid-beta accumulation, oxidative stress, mitochondrial dysfunction, and neuroinflammation. Obesity is characterized by increasing pro-inflammatory cytokines secretions from adipose tissue, which stimulate macrophages and lymphocytes and eventually lead to local and systemic inflammation. This inflammation promotes insulin resistance, hyperinsulinemia, and as a consequence, hyperglycemia. Obesity is a well-known risk factor for type 2 diabetes, CVDs, and cancer, which are identified as risk factors for dementia and AD. The brain inflammation causes an increase in microglia and results in reduced synaptic plasticity and impaired neurogenesis. Microglia can affect insulin receptor substrate 1 (IRS-1) and block intracellular insulin signaling, which has an important role in neural health. Therefore, alteration in insulin action can result in Aβ accumulation and reduce the tau protein degradation associated with AD [ 91 , 92 , 93 , 94 ].

6. Treatment

Currently, Alzheimer’s disease cases worldwide are reported to be around 24 million, and in 2050, the total number of people with dementia is estimated to increase 4 times. Even though AD is a public health issue, as of now, there is only two classes of drugs approved to treat AD, including inhibitors to cholinesterase enzyme (naturally derived, synthetic and hybrid analogues) and antagonists to N -methyl d -aspartate (NMDA). Several physiological processes in AD destroy Ach-producing cells which reduce cholinergic transmission through the brain. Acetylcholinesterase inhibitors (AChEIs), which are classified as reversible, irreversible, and pseudo-reversible, act by blocking cholinesterase enzymes (AChE and butyrylcholinesterase (BChE)) from breaking down ACh, which results in increasing ACh levels in the synaptic cleft [ 95 , 96 , 97 ]. On the other hand, overactivation of NMDAR leads to increasing levels of influxed Ca 2+ , which promotes cell death and synaptic dysfunction. NMDAR antagonist prevents overactivation of NMDAR glutamate receptor and hence, Ca 2+ influx, and restores its normal activity. Despite the therapeutic effect of these two classes, they are effective only in treating the symptoms of AD, but do not cure or prevent the disease [ 98 , 99 ]. Unfortunately, only a few clinical trials on AD have been launched in the last decade and their outcome was a big failure. Several mechanisms have been proposed to understand AD pathology in order to modify its pathway and develop successful treatments, which include abnormal tau protein metabolism, β-amyloid, inflammatory response, and cholinergic and free radical damage [ 30 , 100 ]. On the other hand, most AD modifiable risk factors such as cardiovascular or lifestyle habits can be prevented without medical intervention. Studies showed that physical activity can improve the brain health and reduce AD by activating the brain vascularization, plasticity, neurogenesis, and reducing inflammation by decreasing Aβ production, which all result in improving cognitive function in older people. Moreover, the Mediterranean diet (MD), intellectual activity, and higher education all may reduce the progression of AD and memory loss and increase the brain capacity and cognitive functions. Several studies revealed that multi-domain intervention which includes lifestyle (diet, exercise, and cognitive training), depression of AD symptoms, and controlling cardiovascular risk factors, can increase or maintain cognitive function and prevent new cases of AD in older people [ 101 ]. Herein, we summarize the currently available drugs and theories for the development of new therapies for AD.

6.1. Symptomatic Treatment of AD

6.1.1. cholinesterase inhibitors.

According to the cholinergic hypothesis, AD is due to the reduction in acetylcholine (ACh) biosynthesis. Increasing cholinergic levels by inhibiting acetylcholinesterase (AChE) is considered one of the therapeutic strategies that increases cognitive and neural cell function. AChEIs are used to inhibit acetylcholine degradation in the synapses, which results in continuous accumulation of ACh and activation of cholinergic receptors. Tacrine (tetrahydroaminoacridine) ( 1, Figure 4 ) was the first FDA (Food and Drug Administration)-approved cholinesterase inhibitor drug for the treatment of AD, which acts by increasing ACh in muscarinic neurons, but it exited the market immediately after its introduction due to a high incidence of side effects like hepatotoxicity and a lack of benefits, which was observed in several trials. Later on, several AChEIs were introduced, such as donepezil ( 2 , Figure 4 ), rivastigmine ( 3 , Figure 4 ), and galantamine ( 4 , Figure 4 ), and are currently in use for the symptomatic treatment of AD [ 34 , 97 , 102 , 103 ]. Another strategy that may help in the treatment of AD is increasing choline reuptake and as a result, increasing acetylcholine synthesis at the presynaptic terminals. This can be achieved by targeting choline transporter (CHT1) which is responsible for supplying choline for the synthesis of ACh. Developing drugs that are capable of increasing CHT1 at the plasma membrane may become the future therapy of AD [ 36 ].

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The chemical structures of approved drugs for symptomatic treatment of AD (tacrine 1 , donepezil 2 , rivastigmine 3 , galantamine 4 , and memantine 5 ) and disease-modifying compounds that entered clinical trials (semagacestat 6 , avagacestat 7 , tarenflurbil 8 , lanabecestat 9 , verubecestat 10 , atabecestat 11 , umibecestat 12 , methylene blue 13 , tideglusib 14 , and saracatinibin 15 ).

Donepezil ( 2 , Figure 4 ) is an indanonebenzylpiperidine derivative and a second generation of AChEIs and is considered the leading drug for AD treatment. Donepezil binds to acetylcholinesterase reversibly and inhibits acetylcholine hydrolysis, which leads to a higher concentration of ACh at the synapses. The drug is well-tolerated with mild and transient cholinergic side effects which are related to the gastrointestinal and nervous systems. It should be noted that donepezil is used to treat symptoms of AD such as improving cognition and behavior without altering the AD progression [ 104 , 105 , 106 ].

  • Rivastigmine

Rivastigmine ( 3 , Figure 4 ) is a pseudo irreversible inhibitor of AChE and butyrylcholinesterase (BuChE) that acts by binding to the two active sites of AChE (anionic and estearic sites), which results in preventing ACh metabolism. BuChE is found mostly in glial cells with only 10% of AChE activity in the normal brain, whereas in the AD brain, its activity is increased to 40–90%, while ACh activity is reduced simultaneously, which suggests that BuChE action may indicate a moderate to severe dementia. Rivastigmine dissociates more slowly than AChE, which is why it is called a pseudo-irreversible, and it undergoes metabolism at the synapse by AChE and BuChE. The drug is used in mild to moderate AD cases. It improves cognitive functions and daily life activities. Oral administration of the drug is associated with adverse effects such as nausea, vomiting, dyspepsia, asthenia, anorexia, and weight loss. In many cases, these side effects are the main reason behind stopping taking the medicine, however, they can be settled down in time and consequently, the drug becomes more tolerated. Rivastigmine can be delivered by transdermal patches for controlled and continuous delivery of the drug through the skin, with enhanced tolerability and caregiver satisfaction. Also, the patches can deliver a lower dosage compared to pills, which results in reduced side effects. Most AD patients suffer from memory loss and swallowing problems which affect their compliance in administering oral drugs at regular intervals. Therefore, the use of transdermal patches is the most appropriate method for delivering the drug in AD patients [ 107 , 108 , 109 , 110 ].

  • Galantamine (GAL)

Galantamine ( 4 , Figure 4 ) is considered a standard first-line drug for mild to moderate AD cases. GAL is a selective tertiary isoquinoline alkaloid with a dual mechanism of action in which it acts as a competitive inhibitor of AChE and can bind allosterically to the α-subunit of nicotinic acetylcholine receptors and activate them. GAL can improve behavioral symptoms, daily life activities, and cognitive performance with good efficacy and tolerability, similar to other AChE inhibitors. Several delivery systems were developed to improve the drug delivery to the brain: Wahba et al. attached GAL to ceria-containing hydroxyapatite particles for selective delivery of the drug to the affected regions in the brain. Misra et al. and Fornaguera et al. used solid-lipid nanoparticles and nano-emulsification approaches respectively, to carry GAL hydrobromide. The results of these studies demonstrated a promising strategy for safe delivery of the drug. Hanafy et al. developed nasal GAL hydrobromide/chitosan complex nanoparticles which showed good pharmacological efficacy, while Woo et al. utilized the patch system as a carrier for a controlled release dosage form of the drug [ 111 , 112 , 113 , 114 ].

6.1.2. N -methyl d -aspartate (NMDA) Antagonists

NMDAR is believed to have a dominant role in the pathophysiology of AD. NMDAR stimulation results in Ca 2+ influx which activates signal transduction and as a consequence, it triggers gene transcription essential for the formation of a long-term potentiation (LTP), which is important for synaptic neurotransmission, plasticity, and memory formation. Over-activation of NMDARs causes an abnormal level of Ca 2+ signaling and overstimulation of glutamate, which is the primary excitatory amino acid in the CNS, which results in excitotoxicity, synaptic dysfunction, neuronal cell death, and a decline in cognitive functions. Several NMDAR uncompetitive antagonists have been developed and entered clinical trials, however, most of them failed due to low efficacy and side effects. Memantine ( 5 , Figure 4 ) is the only approved drug in this category to treat moderate to severe AD; in addition, other NMDAR uncompetitive antagonist compounds are being developed, such as RL-208 (3,4,8,9-tetramethyltetracyclo [4.4.0.0 3,9 .0 4,8 ]dec-1-yl)methylamine hydrochloride), a polycyclic amine compound that may possess a promising therapeutic effect in age-related cognitive problems and AD [ 115 , 116 , 117 ].

Memantine ( 5 , Figure 4 ) is a low-affinity uncompetitive antagonist of the NMDAR, a subtype of glutamate receptor that prevents over-activation of the glutaminergic system involved in the neurotoxicity in AD cases. Memantine is used for the treatment of moderate to severe AD alone or in combination with AChEI. The drug is safe and well-tolerated, it blocks the excitatory receptor without interfering with the normal synaptic transmission due to memantine’s low affinity, where it is displaced rapidly from NMDAR by high concentrations of glutamate, thus avoiding a prolonged blockage. The latter is associated with high side effects, especially on learning and memory [ 99 , 118 ].

6.2. Promising Future Therapies

6.2.1. disease-modifying therapeutics (dmt).

Disease-modifying treatment or therapy (DMT) alter the progression of AD by working on several pathophysiological mechanisms. This is in contrast to symptomatic therapy which works on improving the cognitive functions and decreasing symptoms such as depression or delusions without affecting or modifying the disease. DMTs, either immunotherapies or small molecules, are administrated orally and are being developed to prevent AD or decrease its progression. Several DMTs have been developed and entered the clinical trials, such as AN-1792, a synthetic Aβ peptide (human Aβ 1–42 peptide of 42-amino acids with the immune adjuvant QS-21) and the first active immunotherapy for AD which entered phase II clinical trials and discontinued due to a meningoencephalitis side effect in 6% of the patients. Other drugs were also developed and failed in the clinical trials, including the anti-Aβ antibody (solanezumab and bapineuzumab), γ-Secretase inhibitors (semagacestat 6 , avagacestat 7 , and tarenflurbil 8 ) ( Figure 4 ) and β-secretase inhibitors (BACE) (Lanabecestat 9, verubecestat 10 , and atabecestat 11 ) ( Figure 4 ). DMTs failures are due to several factors, such as starting therapy too late, giving treatment for the wrong main target, use of inappropriate drug doses, and misunderstanding of the pathophysiology of AD. Several immunotherapies described in Table 1 have been developed over decades, including: CAD106, an active Aβ immunotherapy that induces Aβ antibodies in animal models and consists of multiple copies of Aβ1–6 peptide coupled to Qβ coat protein, a virus-like particle, and is still in clinical trials, and CNP520 (umibecestat, 12 ) ( Figure 4 ), a small molecule that inhibits beta-scretase-1 (BACE-1) and therefore inhibits Aβ production. CNP520 was found to reduce Aβ plaque deposition and Aβ levels in the brain and CSF in rats, dogs, and healthy adults ≥ 60 years old, and is still under clinical trials. Furthermore, aducanumab, gantenerumab, and crenezumab are all human Aβ monoclonal antibody that bind with high affinity to aggregated Aβ, and they are still under study in the clinical phases with other DMTs described in Table 1 [ 6 , 119 , 120 , 121 , 122 , 123 , 124 ].

Disease modifying agents for the treatment of Alzheimer’s disease in clinical trials.

Another class targeting the α-secretase enzyme was developed and has been considered as therapeutic agents. α-secretase modulators or activators stimulate the cleavage of APP. There is little knowledge about the activation pathway, but research assumes that it is promoted by the phosphatidylinositol 3-kinase (PI3K)/Akt pathway or by γ-aminobutyric acid (GABA) receptor signaling. Targeting these pathways may give potential therapeutic agents for AD [ 6 ].

In addition to the anti-amyloid agents, the tau aggregation inhibitors are another promising DMT. The tau is a biomarker for neurofibrillary tangles (NFT) in AD and naturally modulates microtubule stability, signaling pathways, and axonal transport. A modification in tau conformation results in toxic aggregation. Therefore, the prevention of tau aggregation becomes an interesting approach for drug discovery to reduce AD progression. Studies in mice have shown that tau oligomers cause mitochondrial damage, disruption of neuronal signaling, synaptic loss, and memory impairment. Disease-modifying therapeutics (DMT) like small molecules can be used to inhibit the initial step in the tau aggregation and thereby reduce its accumulation. Methylene blue ( 13 , Figure 4 ) is a blue dye that inhibits the tau aggregation and entered phase II clinical trials to treat mild to moderate AD. Upon administration of the drug, the color of the urine becomes blue, which indicates a lack of binding, and because of that, the study was highly criticized. Other approaches suggest that an inhibition of specific kinases such as glycogen synthase kinase 3 (GSK3β) can inhibit tau hyperphosphorylation and block tau deposition. Examples of these entities include tideglusib ( 14 , or NP-031112 (NP-12), Figure 4 ), a thiazolidinedione-derived compound, lithium, pyrazolopyridines, pyrazolopyrazines, sodium valproate, and others. Another protein kinase inhibitor is saracatinib (AZD0530) ( 15 , Figure 4 ), which acts by inhibiting tyrosine kinase and has shown good results in improving memory in transgenic mice and is currently in phase II trials [ 125 , 126 , 127 ]. Davidowitz et al. utilized the hatu mouse model of tauopathy to study the efficacy of a lead small molecule in preventing tau accumulation. The study results demonstrated a significant reduction in tau levels and its phosphorylated form levels, which indicates the ability to inhibit the entire pathway of the tau aggregation by using an optimized lead compound [ 128 ].

6.2.2. Chaperones

Protein misfolding caused by mutations or environmental factors results in aggregations that are toxic, and their accumulation causes neurodegenerative disorders like AD. Naturally, cells develop protein quality control (PQC) systems that inhibit protein misfolding before exerting their toxic effects. With age, this balance is altered and the misfolded shapes overwhelm the PQC system, which in turn activates the unfolded protein response (UPR) that stops the protein synthesis and increases chaperone production. Generally, the cells in humans have proteins that are responsible for other proteins to function and arrive to their destination in the cell. These proteins are called “chaperones”. Chaperones are involved in protein folding and improvement of the PQC system efficiency. Therefore, it is considered a promising candidate for treating neurodegenerative diseases. It can be classified into three groups: (1) molecular chaperones, which are proteins that assist other nonnative proteins in their folding or unfolding, like overexpression of heat shock proteins (Hsps) that serve as neuroprotective agents, (2) pharmacological chaperones, which are low molecular weight compounds (enzymes or receptor-ligand or selective binding molecules) that induce refolding of proteins, stabilize their structure, and restore their function, and (3) chemical chaperones, also low molecular weight compounds, which are divided into two groups, osmolytes and hydrophobic compounds. The members in these two groups have no specific mechanism of action and need high concentrations to exert their therapeutic effects [ 129 ].

  • Heat Shock Proteins (Hsps)

The causes for most neurodegenerative diseases are protein misfolding and aggregation, which lead to cell death. The molecular chaperone can be intracellular, such as in the case of heat shock proteins (e.g., Hsp40, Hsp60, Hsp70, Hsp90, Hsp100, and Hsp110), and extracellular, such as clustering and alpha-macroglobulin. HSPs play an essential role in the protein folding process and protect cells from harmful stress-related events. There are two families of Hsps: (a) classic Hsps that possess an ATP-binding site with a molecular weight of 60 kD or more. This family includes Hsp100, Hsp90, Hsp70, and Hsp60, and (b) the small Hsps such as αB-crystalline, Hsp27, Hsp20, HspB8, and HspB2/B3 that lack ATP-binding site, with a molecular weight of 40 kD or less. These proteins can assist other Hsps in their refolding function. Failure of these mechanisms can lead to oxidative stress, mitochondrial dysfunction, and many other conditions that cause damage, a loss of neurons, and a progression of neurodegenerative diseases. Different HSPs can block the aggregation process of misfolded proteins, like amyloidogenic proteins (Aβ and tau), and promote their degradation [ 130 , 131 ].

Hsp60 plays an important role in mitochondrial protein folding. Its role in AD is not clear, some believe that the protein has a protective role and others think it has a harmful effect where it can be over-expressed by activated microglia, which increases pro-inflammatory factors such as toll-like receptor 4 (TLR-4) that stimulate neuronal cell death. Therefore, inhibiting activated microglia and Hsp60 expression is a promising strategy for preventing neurodegenerative diseases. Examples of compounds that inhibit Hsp60 are mizoribine (Immunosuppressant) ( 16 , Figure 5 ) and pyrazolopyrimidine EC3016 ( 17 , Figure 5 ). Both compounds act by blocking ATPase activity of Hsp60 and inhibiting protein folding. On the other hand, avrainvillamide, a fungal metabolite ( 18 , Figure 5 ), and epolactaene, a bacterial metabolite ( 19 , Figure 5 ), act by binding to the Hsp60′s cysteine residues and inhibit its folding activity. However, Hsp60’s role in AD remains controversial and there is a need for more investigations to understand its role [ 130 ].

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The chemical structures of different chaperone molecules: Mizoribine 16 , EC3016 17 , Avrainvillamide 18 , Epolaztaene 19 , MKT-077 20 , YM-01 21 , JG-98 22 , Radicicol 23 , Geldanamycin 24 , 17-AAG 25 , Pochoxime C (OS47720) 26 , R55 27 , and OT1001 28 .

Studies have shown that Hsp70 binds to Aβ42 and prevents self-aggregation. Martín-Peña et al. studied two isoforms of Hsp70, cytosolic and extracellular, in Drosophila flies AD models and evaluated their protective role against memory decline that results from Aβ42 aggregation. The animal studies showed that Hsp70 has a dual function: intracellularly and extracellularly, where it protects against Aβ42 neurotoxicity and synaptic loss. In addition to its ability to bind to tau and its hyper-phosphorylated form and prevent its formation, it decreases aggregation and promotes tau binding to microtubules. Hsp70 acts by activating microglia, insulin-degrading enzyme, and tumor growth facto r- β1, which degrades β-amyloids and prevents memory impairments [ 132 , 133 ]. Some studies in AD brain tissue demonstrated an overexpression of Hsp70 levels and a correlation with the presence of activated glia and stressed neurons. Also, it was found that Hsp70 is associated with extracellular deposits in AD. Drug therapies targeting Hsp70, mainly referring to previous anticancer drugs which target and inhibit Hsp70 ATP-binding site, are considered as candidates in AD treatment due to their ability to reduce tau levels in vitro and ex vivo. MKT-077(1-ethyl-2-(( Z )-(( E )-3-ethyl-5-(3-methylbenzo [ d ]thiazol-2(3 H )-ylidene)-4-oxothiazolidin-2-ylidene)methyl)pyridin-1-ium chloride) ( 20 , Figure 5 ), is an anticancer rhodacyanine compound that binds to mortalin, a mitochondrial Hsp70 site, and acts as an anti-proliferative agent, but the use of this compound was stopped due to toxicity side effects and low BBB penetration. On the other hand, YM-01 ( 21 , Figure 5 ), a more potent MKT-077 derivative, was developed with a single replacement of the ethyl group on the pyridinium nitrogen of MKT-077 with a methyl group. JG-98 ( 22 , Figure 5 ) is also an MKT-077 derivative with a 60-fold higher binding affinity to Hsp70 than YM-01 [ 130 , 134 , 135 , 136 ].

Hsp90 is another type of HSP that regulates the tau phosphorylation and dephosphorylation. An inhibition of Hsp90 results in a decrease in phosphorylation of tau due to a reduction in tau kinases, which is thought to be responsible for tau pathogenesis when it is hyperactivated. Hsp90 inhibitors are used for cancer therapy, but recently, they are considered as promising therapy for AD. Radicicol (RDC) ( 23 , Figure 5 ) and geldanamycin (GA) ( 24 , Figure 5 ) are Hsp90 inhibitors. GA is a natural antifungal compound and the first discovered Hsp90 inhibitor. Studies on this inhibitor were stopped due to its toxicity. On the other hand, 17-AAG (17-(Allylamino)-17-demethoxygeldanamycin) ( 25 , Figure 5 ) is a GA derivative with a lower toxicity and better pharmacokinetic profile that showed a good improvement of the cognitive function by inducing other HSPs, like Hsp70, in addition to reducing NFTs in the transgenic mouse model by blocking the tau phosphorylation pathway, indirectly [ 137 , 138 ]. Pochoxime C (OS47720) ( 26 , Figure 5 ) is also a CNS-permeable Hsp90 inhibitor that showed good safety and efficacy profiles when tested in the AD mouse model. Studies revealed that OS47720 acts by strengthening synaptic function via heat shock factor (HSF-1) activation and dependent transcriptional events [ 139 ].

The combined studies demonstrate that targeting HSPs is a promising strategy to develop drugs with a new mechanism of action for reducing pathogenic tau levels and restoring normal tau homeostasis.

  • Vacuolar sorting protein 35 (VPS35)

An accumulation of proteins in neurons and glial cells leads to disturbance of cellular protein homeostasis. The endosomal-lysosomal system is responsible for transporting proteins for recycling and degradation. Any malfunction in the system can lead to several diseases, such as Alzheimer’s disease. Retromer is a complex of regulator proteins composed of sorting nexin (SNX1, 2, 5, 6) and vacuolar sorting proteins (VPS 26, 29, 35), which are responsible for transporting cargo molecules from the endosome to the trans -Golgi network. A loss of retromer’s function results in the downregulation of VPS35, which can increase Aβ formation, induce cognitive impairments, and cause synaptic dysfunction, which is reported in AD patients [ 140 , 141 ]. A study on 3xTg mice brains was conducted to evaluate the effect of VPS35 overexpression on memory function. The study showed that a significant reduction of the Aβ peptide and tau neuropathology (soluble, insoluble, and phosphorylated tau) was associated with overexpression of VPS35, in addition to a reduction in neuroinflammation and ameliorating synaptic dysfunction [ 142 ]. Therefore, VPS35 is an important promising therapeutic target for AD treatment. A small pharmacological chaperones molecule called R55 (thiophene-2,5-diylbis(methylene) dicarbamimidothioatedihydrochloride) ( 27 , Figure 5 ), a thiophenethiourea derivative, can enhance retromer stability and function by increasing retromer proteins, shifting AOO from the endosome, and reducing pathogenic processing of APP, which may serve as a promising therapeutic molecule for neurodegenerative diseases [ 143 ].

Studies demonstrated that the accumulation of gangliosides has been associated with misfolding and aggregation of proteins in neurodegenerative diseases. Abnormal levels of mono-sialoganglioside (GM1, GM2, and GM3) have been reported in AD brains. Mutant forms of Aβ, like Dutch mutant APPE693Q, showed susceptibility to pro-aggregation properties of GM2 and GM3, resulting in the formation of Aβ peptides complexes with gangliosides (ganglioside-bound Aβ (GAβ) peptide) and subsequently leading to an acceleration of aggregation and accumulation of Aβ peptides.

β-hexosaminidase (β-hex) is a lysosomal enzyme that acts by catabolizing GM2 ganglioside, and increasing its activity can lead to a reduction of GM2 levels and Aβ aggregation and accumulation. Small molecules like pharmacological chaperones (PC) can selectively bind and stabilize wild-type proteins and restore their normal folding. OT1001 ( 28 , Figure 5 ) is an iminosugar PC that targets β-hex and increases its level in the brain and reduces GAβ pathology. Studies on Dutch APPE693Q transgenic mice showed that OT1001 has good pharmacokinetics, brain penetration ability, and tolerability, with lower side effects. These make the compound a good drug candidate for increasing the β-hex activity [ 144 ].

6.2.3. Natural Extract

For a long time, natural compounds have been used as therapeutic agents for several pathological diseases, and recent studies showed that they possess a neuroprotective effect. In vitro and in vivo studies have proven that natural compounds possess a therapeutic potential for AD, which allowed some of them to enter the clinical trials stages. Nicotine was the first natural compound entered in the clinical trials for AD, then other compounds like vitamins C, E, and D gained more attention and interest due to their protective role against neuroinflammation and oxidative damage. Recently, bryostatin, a macrolide lactone extract from bryozoan Bugula neritina, has been evaluated and showed the ability to induce α-secretase activity, reduce Aβ production, and enhance the learning and memory in an AD mice model [ 145 ]. Other natural compounds used in folk medicine (traditional Chinese medicine (TCM)) demonstrated a great potential in treating AD by acting on several mechanisms, as shown in Table 2 below [ 146 ].

Natural compounds used in folk medicine and their mechanism of actions.

7. Conclusions

Alzheimer’s disease is now considered a world health concern; as a consequence, the National Institute on Aging—Alzheimer’s Association reclassified and updated the 1984 NINCDS-ADRDA criteria for higher specificity, sensitivity, and early identification of patients at risk of developing AD. Several criteria have been proposed for a more accurate diagnosis of AD, including clinical biomarkers, bodily fluids, and imaging studies. Despite that, the treatment of AD remains symptomatic, without alteration in the disease’s prognosis. Inhibitors to cholinesterase enzyme such as galantamine, donepezil, and rivastigmine, and NMDA antagonists such as memantine, improve memory and alertness but do not prevent progression. Several studies have shown that modification in lifestyle habits like diet and exercise can improve brain health and reduce AD without medical intervention and is considered as a first-line intervention for all AD patients. Recently, the research is focusing on targeting the pathological features of AD such as Aβ and p-tau. Future therapies such as disease-modifying treatment can alter the progression of AD by targeting the Aβ pathway, and many drugs have entered the clinical trials, like AN-1792, solanezumab, bapineuzumab, semagacestat, avagacestat, and tarenflurbil, but failed in demonstrating efficacy in the final clinical stages. Other DMTs are still under investigation, such as those targeting Aβ and tau pathologies, such as aducanumab, gantenerumab, crenezumab, tideglusib, lithium, and others. Other promising compounds called chaperones like heat shock proteins and vacuolar sorting protein 35 (VPS35) function by assisting other proteins to function normally and to arrive at their destination in the cell safely, and therefore can be used as a treatment for neurodegenerative diseases. Moreover, the natural extracts used in folk Chinese medicine showed great potential in treating AD by acting on several mechanisms’ pathways. In conclusion, the success of AD treatment depends on its early administration and patient monitoring for disease progression using biomarkers diagnosis. Future therapies that target tau pathology and the use of combination therapy may have a potential to slow the progression of AD pathology. Designing a potent, selective, and effective drug is urgently needed to treat patients with AD and those at risk for developing the disease.

Author Contributions

Literature survey and first draft writing were done by Z.B., and final draft, including the revisions, were accomplished by R.K. All authors have read and agreed to the published version of the manuscript.

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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The brain that defied alzheimer’s.

Genetic mutation found that could shed light on mechanism for disease resistance, lead to new therapies

Neil Osterweil

MGH News and Public Affairs

Illustration by Roy Scott

Aliria Rosa Piedrahita de Villegas should have developed Alzheimer’s disease in her 40s and died from the disease in her 60s because of a rare genetic mutation.

Instead, she lived dementia-free into her 70s, and now her brain is yielding important clues about the pathology of dementia and possible treatments for Alzheimer’s disease.

As researchers at Massachusetts General Hospital and other centers first described in 2019, the woman, from Medellin, Colombia, was a member of an extended family with a mutation in a gene labeled PSEN1. The PSEN1 E280A mutation is autosomal dominant, meaning that only a single copy of the gene is required to cause disease. Carriers of the mutation typically exhibit symptoms of Alzheimer’s in their 40s or 50s, and die from the disease soon after, but this woman did not begin to show signs of Alzheimer’s until her early 70s. She died in 2020 from metastatic melanoma at the age of 77.

The key difference in the Colombian woman’s ability to fend off the disease for three decades appeared to be that in addition to having the PSEN1 E280A mutation, she was also a carrier of both copies of a mutation known as APOE3 Christchurch.

“This exceptional case is an experiment designed by nature that teaches us a way to prevent Alzheimer’s: let’s observe, learn, and imitate nature.” Francisco Lopera, director of the Neuroscience Group of Antioquia in Medellín, Colombia.

The APOE family of genes control production of apolipoproteins, which transport lipids (fats) in blood and other bodily fluids. The APOE2 variant is known to be protective against Alzheimer’s dementia, while the APOE4 variant is linked to an increased risk for the disease.

APOE3, the most common variant, is not typically associated with either reduced or increased risk for Alzheimer’s.

“This is a ground-breaking case for Alzheimer’s disease and has already opened new paths for treatment and prevention, which we’re currently pursuing with some collaborators. This work is now bringing light into some of the mechanisms of resistance to Alzheimer’s disease” says investigator Yakeel T. Quiroz

Quiroz is director of the  Multicultural Alzheimer Prevention Program (MAPP ) at Mass General, an associate professor of psychology at Harvard Medical School, and  Paul B. and Sandra M. Edgerley MGH Research Scholar 2020-2025 .

As Quiroz and colleagues now report in the neuropathology journal  Acta Neuropathologica , the woman did, in fact, have pathologic features of Alzheimer’s disease in her brain, but not in regions of the brain where the hallmarks of Alzheimer’s are typically found.

“This patient gave us a window into many competing forces — abnormal protein accumulation, inflammation, lipid metabolism, homeostatic mechanisms — that either promote or protect against disease progression, and begin to explain why some brain regions were spared while others were not,” says Justin Sanchez, co-first author, and an investigator at MGH Neurology.

Researchers identified in Aliria’s brain a distinct pattern of abnormal aggregation or “clumping” of  tau, a protein known to be altered in Alzheimer’s disease and other neurologic disorders.

In this case, the tau pathology largely spared the frontal cortex, which is important for judgment and other “executive” functions, and the hippocampus, which is important for memory and learning. Instead, the tau pathology involved the occipital cortex, the area of the brain at the back of the head that controls visual perception.

The occipital cortex was the only major brain region to exhibit typical Alzheimer’s features, such as chronic inflammation of protective brain cells called microglia, and reduced levels of APOE expression.

“Thus, the Christchurch variant may impact the distribution of tau pathology, modulates age at onset, severity, progression, and clinical presentation of [autosomal dominant Alzheimer’s disease], suggesting possible therapeutic strategies,” the researchers write.

“It is seldom that we have nice surprises while studying familial Alzheimer’s disease brains. This case showed an amazingly clear protected phenotype. I am sure our molecular and pathologic findings will at least suggest some avenues of research and elicit hope for a successful treatment against this disorder.” says co-first author Diego Sepulveda-Falla, research lead at University Medical Center Hamburg-Eppendorf in Hamburg, Germany.

“This exceptional case is an experiment designed by nature that teaches us a way to prevent Alzheimer’s: let’s observe, learn, and imitate nature,” concludes Francisco Lopera, director of the Neuroscience Group of Antioquia in Medellín, Colombia. Lopera is a co-senior author and the neurologist who discovered this family and has been following them for the last 30 years.

Quiroz is a co-senior author of the report, along with Kenneth S. Kosik, University of California, Santa Barbara; Lopera, and Sepulveda-Falla. Sanchez contributed equally to the study.

The study was supported by grants from the National Institutes of Health, MGH Executive Committee on Research (MGH Research Scholar Award), Alzheimer’s Association, the Deutsche Forschungsgemeinschaft, Universidad de Antioquia, the Werner Otto Stiftung, and the Gernam Federal Ministiry of Education and Research.

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The Powerful Case for Redefining Alzheimer’s Disease

a case study of alzheimer disease

The signature case of Alzheimer’s disease was a German woman named Auguste whose mental status began to deteriorate to the extent that her husband brought her to a psychiatry clinic in Frankfurt. As is traditional, the scientific literature until very recently referred to Auguste merely by her first name plus the initial of her last name — Auguste D. She was seen at the Frankfurt psychiatric hospital in 1901, and her attending physician at the time was a young 30-something anatomist turned psychiatrist, Alois Alzheimer. Alzheimer came to this case from early interests in the structure of the brain, basically its anatomy and cellular structure. This very structure-based view of brain function was the context he brought to his clinical experiences in psychiatry, a craft he learned under the guidance of Dr. Emil Sioli in Frankfurt-am-Main.

a case study of alzheimer disease

In April 1906, his old mentor Dr. Sioli sent word to Alzheimer that Auguste D. had died. Alzheimer was pleased to learn that Sioli had arranged for an autopsy and had sent tissue from the brain of the deceased woman to Munich for Alzheimer to examine.

Two features of the preparation in particular caught his eye. The first he described in this way: “Throughout the whole cortex … one finds miliar foci, which are caused by deposition of a peculiar substance in the cortex.” The “peculiar substance” we now know was a waxy form of aggregated protein known as amyloid. The “depositions” would come to be known as amyloid plaques. The second feature he described thusly: “very peculiar changes in the neurofibrils … only a tangle of fibrils indicates where a nerve cell had been previously located.” These peculiar neurofibrils are actually aggregates of a different protein known as tau. We now refer to these aggregates as neurofibrillary tangles.

In this way the odd deposits now known as plaques and tangles became tightly linked to a specific form of dementia. Alzheimer made detailed notes on his discovery and took them to his superior, Emil Kraepelin. He was quite certain that the plaques and tangles were the explanation for the highly unusual behavior of Auguste D. Kraepelin apparently liked the idea enough that he suggested that Alzheimer present his findings at a meeting of German psychiatrists in the fall of 1906. Alzheimer agreed and went to Tübingen that fall to announce his discovery.

The original observation was an important case study, but it was elevated to the level of a disease for reasons that were strategic, not scientific.

The story might have ended here as a long-forgotten case study gathering dust in the archives of medicine. Alzheimer’s boss Kraepelin, however, had other ideas. He too was a believer in the idea that psychiatric disease was caused by changes in the physical structure of the brain. The novel plaques and tangles that Alzheimer had found in the brain of Auguste D. neatly fit that philosophy. Kraepelin was very well-known at the time, in part because he was the author of a widely used textbook, “Psychiatrie . ” Kraepelin would periodically update his textbook to include the latest findings (and maybe to sell more books), and, as luck would have it, at the time that Alzheimer published his case, Kraepelin was preparing the eighth edition. To add more support to his own philosophy of the brain, he decided to include the case of Auguste D. in his revision. One might imagine it felt awkward to include a simple case study in a widely used textbook. Kraepelin cleverly solved this problem by elevating the case of Auguste D. to the status of a disease. He called it Alzheimer’s disease, and he included this new condition in the 1910 edition of “Psychiatrie.”

This was a bold and almost reckless move that, in retrospect, had a huge and outsized influence on the field. In most cases, I like it when scientists are bold. Put up a clever argument, and let a smart and informed debate refine it or rebuke it. Either way, science advances. Reckless is not so good. A textbook paragraph is much weightier than the same paragraph in a journal article or a meeting presentation. Textbooks impart a feeling of permanence to an entry. Their contents are imbued with the unspoken assertion that they represent settled art and thus are not easily questioned. Putting Auguste’s condition in a textbook as a new disease comes pretty close to reckless because, on the flimsiest of grounds, Kraepelin was trying to put the “Case Closed” stamp on this telling of what he called Alzheimer’s disease. It was to be the first of three inflations in the definition of Alzheimer’s disease.

Let’s go back and consider Alzheimer’s findings in the brain of Auguste D. Two unusual features occurred together. Unusual deposits, plaques and tangles, were correlated with a highly unusual dementia. One possibility to explain the presence of plaques and tangles in the brain of a person with dementia is the one Alzheimer and Kraepelin favored: The plaques and tangles caused the dementia. That fit well with their philosophies that the function of the brain was governed largely by its structure. It most likely explains why Alzheimer championed this first explanation and why Kraepelin was so eager to promote it. But perhaps Auguste D.’s peculiar dementia caused the brain changes that led to plaques and tangles. The plaques didn’t cause the disease; the disease caused the plaques.

a case study of alzheimer disease

I’ve told the story of Alzheimer and Auguste D. in great detail because it tells us a lot about why the field is stuck and why a successful treatment for Alzheimer’s has been so slow in coming. The original observation was an important case study, but it was elevated to the level of a disease for reasons that were strategic, not scientific. Both Kraepelin and Alzheimer were subscribers to a school of thought that held that the structure of the brain was the key to its function, and that if the structure became littered with abnormal deposits, its function would also become abnormal. Finding plaques and tangles in the brain of a person with dementia fit that idea, and putting it forward as a hypothesis was reasonable. From these origins, however, the two psychiatrists inadvertently biased the thinking of subsequent generations of physicians and scientists. Their assertion that the correlation of plaques and dementia represented a causal relationship — plaques caused the dementia — has proven very hard to shake off, despite the shortage of evidence to support it.

For Alzheimer and Kraepelin, the rare form of early-onset dementia they named Alzheimer’s disease was, they believed, caused by the deposits they had seen in the brain of Auguste D. That first linkage of deposits and dementia was the Trojan horse that released the soldiers of the second inflation. Published in 1976, the article most commonly cited as the manifesto of this effort was written by Robert Katzman and bore the fearsome title “Editorial: The Prevalence and Malignancy of Alzheimer Disease: A Major Killer.” Katzman began his two-page editorial by arguing that there was no really significant difference between the relatively rare condition that was known at the time as Alzheimer’s disease and the far more common condition known as senile dementia. He then went on to argue that dementia was badly underdiagnosed as a cause of death. He estimated that if the cause of death were adjusted to honestly reflect this fact, dementia was arguably “a major killer.” The real purpose of the editorial, however, was to argue for equating senile dementia with Alzheimer’s disease. This was a bit of a stretch.

To bolster his case for their equivalence, Katzman cited earlier clinical speculation that Alzheimer’s disease and senile dementia were similar in their symptoms. He also cited a pair of papers published a few years earlier. Katzman wrote, based on his analysis of these two papers, that when comparing the microscopic appearance of the brain of a person who had died with Alzheimer’s disease with one who had died with the more common senile dementia, “The pathological findings are identical — atrophy of the brain, marked loss of neurons, neurofibrillary tangles, granulovacuolar changes, and neuritic (senile) plaques.”

The problem is that this is not exactly what the two papers had claimed. In fact, five cases with clinical dementia (10 percent of the authors’ subjects) could not be diagnosed with confidence by the microscopic appearance of the brain, and 40 percent had changes that would have led to a non-Alzheimer’s diagnosis. In the end, only “50% were considered to be cases of senile dementia showing the histological features of Alzheimer’s disease.” This is hardly a rock on which to build the claim that senile dementia and Alzheimer’s disease are one and the same.

Katzman’s inflated view of Alzheimer’s disease, however, soon took hold. By 1980, it had earned a place in the third edition of the “Diagnostic and Statistical Manual of Mental Disorders (DSM-III).” Subsequently, attempts were made to precisely define the pathology needed for a diagnosis of Alzheimer’s disease. Eventually, there were so many “authoritative” sources on how to diagnose Alzheimer’s disease that a well-meaning clinician could surely have been forgiven for getting frustrated about what this newly inflated condition really was and whether it applied to the elderly person sitting in his or her office.

To attempt to deal with this, a working group was assembled under the auspices of the National Institute on Aging (NIA) and the Alzheimer’s Association (then known as the Alzheimer’s Disease and Related Disorders Association — ADRDA) to formalize the clinical diagnosis of Alzheimer’s disease. The working group came up with a list of criteria to diagnose what they called “PROBABLE Alzheimer’s Disease [all caps is their emphasis].” But the group went one step further. They established criteria for a diagnosis of “DEFINITE” Alzheimer’s disease. For this score, you first had to have a clinical diagnosis of dementia, using the following five criteria: dementia established by clinical examination; deficits in two or more areas of cognition (problem solving, language, attention, etc.); progressive worsening; no disturbance of consciousness; and onset between ages 40 and 90, most often after age 65. But you also needed “histopathologic [i.e., microscopic] evidence obtained from a biopsy or autopsy.” And what did they consider definitive histopathologic evidence? Remarkably, they didn’t say. Our well-meaning clinician had to wait until the following year when a separate summary of the workshop was published.

The details are important to the aficionado, but it’s the big picture that is important to us. Alzheimer’s disease was to be defined by the presence of plaques. Yet plaques are a feature that is not present in 15 percent of the people with a clinical diagnosis of Alzheimer’s, and a feature that is present in people of all ages including 30 percent of elderly people without any cognitive impairment. If this doesn’t make sense to you, it’s because it doesn’t make sense.

Alzheimer’s disease is defined by the presence of plaques, a feature that is present in people of all ages, including 30 percent of elderly people without any cognitive impairment.

So, who died and made the pathologist king? There was really no good reason for pathology to trump neurology. You can get a definitive diagnosis of any number of complex brain diseases — autism, depression, schizophrenia, epilepsy, and many others — without any pathological study or live imaging of the brain. If a child psychiatrist diagnoses a young boy as having autism, there is no need for a brain scan to test the psychiatrist’s skill. For the purposes of treatment, the child has autism. If a neurologist diagnoses a person as having Parkinson’s, that’s the diagnosis. They don’t wait with bated breath to find out whether there were α-synuclein deposits in the brain. For the purposes of treatment, the person has Parkinson’s disease. Late-life diseases like Parkinson’s and Huntington’s do have characteristic brain abnormalities, but it is the presentation of the clinical symptoms that allows physicians to have confidence in their diagnosis. To be fair, if an autopsy is done and there are no deposits, the diagnosis is questioned, but not rejected . The clinical diagnosis overrules the pathology. As it should.

Then our clinical trials started failing, our antibody trials in particular. In the basic research laboratories of the world, data kept accumulating that violated the expectations of an amyloid-only definition for Alzheimer’s disease biology. In response the NIA began to recognize that there was a “broad consensus … that the criteria should be revised to incorporate state-of-the-art scientific knowledge.” The result was a truly comprehensive review — a compendium of four papers comprising reports of three working groups plus an introductory summary. Coming as it did, a full quarter century after the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) working group met, it would have been an ideal platform to announce the decision to cut the definition of Alzheimer’s disease loose from the presence of plaques. Instead the experts in the field doubled down and bet the store on amyloid. In doing so, they made the entire situation much, much worse.

Writing the first paper was a clear struggle for its authors. The task before the group was to come up with a recommendation for how practicing physicians should decide whether or not a living person, sitting in front of them in their office, had Alzheimer’s disease. But reading their words, it is quite clear they were not about to be drawn into saying in print that amyloid, or any other “biomarker” (like tau), should be used to define Alzheimer’s disease. They made a clean and explicit separation between a clinical diagnosis of Alzheimer’s disease dementia and what they called the “pathophysiological process of Alzheimer’s disease.” What the group essentially said was that in the clinic the presence or absence of amyloid is just a piece of information that can be helpful in reaching a diagnosis, and nothing more.

The second paper in the series was important for the attempt of the working group to define what is known as MCI (mild cognitive impairment). The goal was a useful one: to try to clinically identify Alzheimer’s disease as early as possible so that treatment could begin when the probability for meaningful impact was the greatest. These authors were a separate group of neurologists. They too wrestled with how to incorporate biomarkers into their recommendations. In the end, they conclude, “Considerable work is needed to validate the criteria that use biomarkers and to standardize biomarker analysis for use in community settings.” Like the clinicians in the first paper, they are willing to say that people who have no evidence of amyloid or tau are “unlikely” to have MCI due to Alzheimer’s disease, but they add the caveat that “… such individuals may still have AD, … [but for these patients] … a search for an alternate cause of the MCI syndrome is warranted.” As with the first group, the MCI paper is arguing that while evidence of amyloid and tau may be useful information, it is not definitive.

a case study of alzheimer disease

The first two papers had basically said that pathology was only one of several things to consider in reaching a diagnosis. The third paper in the series, however, put the pathophysiology front and center in our definition of Alzheimer’s disease. More than that, however, it exploded our definition of Alzheimer’s disease almost beyond recognition. This is the third inflationary event in the history of Alzheimer’s disease, and unfortunately, compared to the expansions ushered in by Kraepelin and later by Katzman, this third inflation was bigger and more destructive to the field.

It wreaked havoc by “redefining the earliest stages of Alzheimer’s disease.” This redefinition created what was in effect a totally new stage of the disease process: preclinical Alzheimer’s disease. By “preclinical” the authors meant that people with plaques in their brain (or the wrong amount of amyloid in their cerebrospinal fluid) are not healthy people. They already have Alzheimer’s disease. They just haven’t started to show the symptoms yet. In this telling of the story, the 30 percent of elderly people who have plaques but also have normal brain function are not simply healthy people with plaques. They are sick people without symptoms.

This may seem to be just semantics, but it’s actually an incredibly audacious claim. About 1 in every 10 people over the age of 65 have some symptoms of Alzheimer’s disease. That’s 10 percent of the elderly. The other 90 percent have normal, age-appropriate brain function. But we’ve already learned that about a third of the people in this cognitively normal group have significant levels of plaques in their brain. Therefore, according to this new expanded definition, they have preclinical Alzheimer’s disease. The authors are essentially arguing that we should increase our estimates of the total number of cases of Alzheimer’s disease by threefold. Worse still, the authors are making this recommendation despite the fact that there are reasonable doubts as to whether or not amyloid causes Alzheimer’s disease. Ah, you may say, but aren’t those doubts just the rantings of a few crazed misfits at the fringes of the field? Not really. We just read about these same doubts in the first two papers in the series.

The authors of the third paper understood that they were redefining Alzheimer’s disease, and they were clearly conflicted about what they were doing. In the final paragraph they admit, “The definitive studies … are likely to take more than a decade to fully accomplish.” Said in plain language, we have this idea, but we don’t have the data to back it up. Still, we are going to go with our gut, upend both basic and clinical research, and you’re going to have to live with it because most of your grant money comes from the NIA and the Alzheimer’s Association and their names are on this paper.

This is a huge problem because the definition of a disease is one of its most important attributes. Without a precise and accurate definition, there is no way to find a cure for any disease. Sadly, throughout the long history of Alzheimer’s disease research, strategy and politics have overruled science in the push to apply the label of Alzheimer’s disease to an ever-larger fraction of age-related cognitive decline and aging. As a result, we are left with basically no definition — or at least none of any value. Being in this situation, we are effectively blocked from making any real progress toward treatment. For proof of this, one needs to look no further than the unbroken string of expensive clinical trial failures. Our political calculus has overruled our common sense and caused us to stop listening to our own data — a clear example of how not to study a disease.

Karl Herrup is Professor of Neurobiology and an Investigator in the Alzheimer’s Disease Research Center at the University of Pittsburgh School of Medicine. He is the author of “ How Not to Study a Disease: The Story of Alzheimer’s ,” from which this article is adapted.

Case Study Unlocks Clues to Rare Resilience to Alzheimer’s Disease

Posted on May 30th, 2023 by Lawrence Tabak, D.D.S., Ph.D.

A brain is covered with a protective shield decorated with DNA and labeled Reelin-COLBOS

Biomedical breakthroughs most often involve slow and steady research in studies involving large numbers of people. But sometimes careful study of even just one truly remarkable person can lead the way to fascinating discoveries with far-reaching implications.

An NIH-funded case study published recently in the journal Nature Medicine falls into this far-reaching category [1]. The report highlights the world’s second person known to have an extreme resilience to a rare genetic form of early onset Alzheimer’s disease. These latest findings in a single man follow a 2019 report of a woman with similar resilience to developing symptoms of Alzheimer’s despite having the same strong genetic predisposition for the disease [2].

The new findings raise important new ideas about the series of steps that may lead to Alzheimer’s and its dementia. They’re also pointing the way to key parts of the brain for cognitive resilience—and potentially new treatment targets—that may one day help to delay or even stop progression of Alzheimer’s.

The man in question is a member of a well-studied extended family from the country of Colombia. This group of related individuals, or kindred, is the largest in the world with a genetic variant called the “Paisa” mutation (or Presenilin-1 E280A ). This Paisa variant follows an autosomal dominant pattern of inheritance, meaning that those with a single altered copy of the rare variant passed down from one parent usually develop mild cognitive impairment around the age of 44. They typically advance to full-blown dementia around the age of 50 and rarely live past the age of 60. This contrasts with the most common form of Alzheimer’s , which usually begins after age 65.

The new findings come from a team led by Yakeel Quiroz , Massachusetts General Hospital, Boston; Joseph Arboleda-Velasquez, Massachusetts Eye and Ear, Boston; Diego Sepulveda-Falla, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; and Francisco Lopera, University of Antioquia, Medellín, Colombia. Lopera first identified this family more than 30 years ago and has been studying them ever since.

In the new case report, the researchers identified a Colombian man who’d been married with two children and retired from his job as a mechanic in his early 60s. Despite carrying the Paisa mutation, his first cognitive assessment at age 67 showed he was cognitively intact, having limited difficulties with verbal learning skills or language. It wasn’t until he turned 70 that he was diagnosed with mild cognitive impairment—more than 20 years later than the expected age for this family—showing some decline in short-term memory and verbal fluency.

At age 73, he enrolled in the Colombia-Boston biomarker research study (COLBOS ). This study is a collaborative project between the University of Antioquia and Massachusetts General Hospital involving approximately 6,000 individuals from the Paisa kindred. About 1,500 of those in the study carry the mutation that sets them up for early Alzheimer’s. As a member of the COLBOS study, the man underwent thorough neuroimaging tests to look for amyloid plaques and tau tangles, both of which are hallmarks of Alzheimer’s.

While this man died at age 74 with Alzheimer’s, the big question is: how did he stave off dementia for so long despite his poor genetic odds? The COLBOS study earlier identified a woman with a similar resilience to Alzheimer’s, which they traced to two copies of a rare, protective genetic variant called Christchurch. This variant affects a gene called apolipoprotein E ( APOE3 ), which is well known for its influence on Alzheimer’s risk. However, the man didn’t carry this same protective variant.

The researchers still thought they’d find an answer in his genome and kept looking. While they found several variants of possible interest, they zeroed in on a single gene variant that they’ve named Reelin-COLBOS . What helped them to narrow it down to this variant is the man also had a sister with the Paisa mutation who only progressed to advanced dementia at age 72. It turned out, in addition to the Paisa variant, the siblings also shared an altered copy of the newly discovered Reelin-COLBOS variant.

This Reelin-COLBOS gene is known to encode a protein that controls signals to chemically modify tau proteins , which form tangles that build up over time in the Alzheimer’s brain and have been linked to memory loss. Reelin is also functionally related to APOE , the gene that was altered in the woman with extreme Alzheimer’s protection. Reelin and APOE both interact with common protein receptors in neurons. Together, the findings add to evidence that signaling pathways influencing tau play an important role in Alzheimer’s pathology and protection.

The neuroimaging exams conducted when the man was age 73 have offered further intriguing clues. They showed that his brain had extensive amyloid plaques. He also had tau tangles in some parts of his brain. But one brain region, called the entorhinal cortex, was notable for having a very minimal amount of those hallmark tau tangles.

The entorhinal cortex is a hub for memory, navigation, and the perception of time. Its degeneration also leads to cognitive impairment and dementia. Studies of the newly identified Reelin-COLBOS variant in Alzheimer’s mouse models also help to confirm that the variant offers its protection by diminishing the pathological modifications of tau.

Overall, the findings in this one individual and his sister highlight the Reelin pathway and brain region as promising targets for future study and development of Alzheimer’s treatments. Quiroz and her colleagues report that they are actively exploring treatment approaches inspired by the Christchurch and Reelin-COLBOS discoveries.

Of course, there’s surely more to discover from continued study of these few individuals and others like them. Other as yet undescribed genetic and environmental factors are likely at play. But the current findings certainly offer some encouraging news for those at risk for Alzheimer’s disease—and a reminder of how much can be learned from careful study of remarkable individuals.

References :

[1] Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man . Lopera F, Marino C, Chandrahas AS, O’Hare M, Reiman EM, Sepulveda-Falla D, Arboleda-Velasquez JF, Quiroz YT, et al. Nat Med. 2023 May;29(5):1243-1252.

[2] Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report . Arboleda-Velasquez JF, Lopera F, O’Hare M, Delgado-Tirado S, Tariot PN, Johnson KA, Reiman EM, Quiroz YT et al. Nat Med. 2019 Nov;25(11):1680-1683.

Alzheimer’s Disease & Related Dementias (National Institute on Aging/NIH)

“ NIH Support Spurs Alzheimer’s Research in Colombia ,” Global Health Matters, January/February 2014, Fogarty International Center/NIS

“ COLBOS Study Reveals Mysteries of Alzheimer’s Disease ,” NIH Record, August 19, 2022.

Yakeel Quiroz (Massachusetts General Hospital, Harvard Medical School, Boston)

Joseph Arboleda-Velasquez (Massachusetts Eye and Ear, Harvard Medical School, Boston)

Diego Sepulveda-Falla Lab (University Medical Center Hamburg-Eppendorf, Hamburg, Germany)

Francisco Lopera (University of Antioquia, Medellín, Colombia)

NIH Support: National Institute on Aging; National Eye Institute; National Institute of Neurological Disorders and Stroke; Office of the Director

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Tags: Alzheimer’s disease , APOE3 , brain , Christchurch variant , cognitive resilience , Colombia , Colombia-Boston biomarker research study , dementia , genetics , genomics , global health , Paisa mutation , Paisa variant , Presinilin-1 , Reelin-COLBOS gene variant , tau , tau protein

One Comment

The entorhinal cortex is a hub for memory, navigation, and the perception of time. Also pheromone reception. 100mg of healthy adult male facial skin surface lipid pheromone that is normally passed in kissing, allows laughing, singing, and real joy again in an Alzheimer’s patient. The pheromone, the grease on your nose, is always in sight whenever your silly eyes are open. It halts the progression of Alzheimer’s Disease, also FT dementia, Tourette’s, Parry-Romberg, epilepsy, …

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Silent brain changes precede Alzheimer’s. Researchers have new clues about which come first

FILE - A closeup of a human brain affected by Alzheimer's disease, is displayed at the Museum of Neuroanatomy at the University at Buffalo in Buffalo, N.Y., on Oct. 7, 2003. According to findings published Wednesday, Feb. 21, 2024 in the New England Journal of Medicine, Alzheimer’s quietly ravages the brain long before symptoms appear and now scientists are getting a closer look at the domino-like sequence of those changes _ a potential window to one day intervene. (AP Photo/David Duprey)

FILE - A closeup of a human brain affected by Alzheimer’s disease, is displayed at the Museum of Neuroanatomy at the University at Buffalo in Buffalo, N.Y., on Oct. 7, 2003. According to findings published Wednesday, Feb. 21, 2024 in the New England Journal of Medicine, Alzheimer’s quietly ravages the brain long before symptoms appear and now scientists are getting a closer look at the domino-like sequence of those changes _ a potential window to one day intervene. (AP Photo/David Duprey)

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WASHINGTON (AP) — Alzheimer’s quietly ravages the brain long before symptoms appear and now scientists have new clues about the dominolike sequence of those changes — a potential window to one day intervene.

A large study in China tracked middle-aged and older adults for 20 years, using regular brain scans, spinal taps and other tests.

Compared to those who remained cognitively healthy, people who eventually developed the mind-robbing disease had higher levels of an Alzheimer’s-linked protein in their spinal fluid 18 years prior to diagnosis, researchers reported Wednesday. Then every few years afterward, the study detected another so-called biomarker of brewing trouble.

Scientists don’t know exactly how Alzheimer’s forms. One early hallmark is that sticky protein called beta-amyloid, which over time builds up into brain-clogging plaques. Amyloid alone isn’t enough to damage memory — plenty of healthy people’s brains harbor a lot of plaque. An abnormal tau protein that forms neuron-killing tangles is one of several co-conspirators.

The new research, published in the New England Journal of Medicine, offers a timeline for how those abnormalities pile up.

The study’s importance “cannot be overstated,” said Dr. Richard Mayeux, an Alzheimer’s specialist at Columbia University who wasn’t involved in the research.

“Knowledge of the timing of these physiological events is critical” for testing new ways of treating and maybe eventually even preventing Alzheimer’s, he wrote in an accompanying editorial.

The findings have no practical implications yet.

More than 6 million Americans, and millions more worldwide, have Alzheimer’s, the most common form of dementia. There’s no cure. But last year a drug named Leqembi became the first approved with clear evidence that it could slow the worsening of early Alzheimer’s — albeit for a few months.

In this photo provided by the WVU Rockefeller Neuroscience Institute, an Alzheimer’s patient undergoes focused ultrasound treatment with the WVU RNI team in Morgantown, W.Va., on Oct. 17, 2023. Scientists have found a way to help Alzheimer’s drugs seep inside the brain faster _ by temporarily breaching its protective shield. (Victor Finomore/WVU Rockefeller Neuroscience Institute via AP)

It works by clearing away some of that gunky amyloid protein. The approach also is being tested to see if it’s possible to delay Alzheimer’s onset if high-risk people are treated before symptoms appear. Still other drugs are being developed to target tau.

Tracking silent brain changes is key for such research. Scientists already knew that in rare, inherited forms of Alzheimer’s that strike younger people, a toxic form of amyloid starts accumulating about two decades ahead of symptoms and at some point later tau kicks in.

The new findings show the order in which such biomarker changes occurred with more common old-age Alzheimer’s.

Researchers with Beijing’s Innovation Center for Neurological Disorders compared 648 people eventually diagnosed with Alzheimer’s and an equal number who remained healthy. The amyloid finding in future Alzheimer’s patients was the first, 18 years or 14 years prior to diagnosis depending on the test used.

Differences in tau were detected next, followed by a marker of trouble in how neurons communicate. A few years after that, differences in brain shrinkage and cognitive test scores between the two groups became apparent, the study found.

“The more we know about viable Alzheimer’s treatment targets and when to address them, the better and faster we will be able to develop new therapies and preventions,” said Claire Sexton, the Alzheimer’s Association’s senior director of scientific programs. She noted that blood tests are coming soon that promise to also help by making it easier to track amyloid and tau.

The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institute’s Science and Educational Media Group. The AP is solely responsible for all content.

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Biomarker Changes during 20 Years Preceding Alzheimer's Disease

Affiliation.

  • 1 From the Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital (J.J., Y.N., M.C., Shuheng Wang, H.Y., F. Li, J.D., Yan Li, B.Z., W.Q., Q.W., Ying Li), Beijing Key Laboratory of Geriatric Cognitive Disorders, Clinical Center for Neurodegenerative Disease and Memory Impairment (J.J.), the Center of Alzheimer's Disease, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders (J.J.), and the Department of Neurology, Beijing Anding Hospital (Y.W.), Capital Medical University, Key Laboratory of Neurodegenerative Diseases, Ministry of Education (J.J.), the Center for Cognitive Disorders, Beijing Geriatric Hospital (J.L.), and the Department of Neurology, Beijing Jishuitan Hospital (X.Y.), Beijing, the Department of Neurology, Daqing Oilfield General Hospital, Daqing (S.Y.), the Department of Neurology, the 960th Hospital of the People's Liberation Army, Jinan (J.Z.), the Department of Neurology, Baotou Central Hospital, Baotou (F. Liang), the Department of Psychiatry, Zhejiang Provincial People's Hospital, Hangzhou (Z.L.), and the Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang (Shan Wang) - all in China.
  • PMID: 38381674
  • DOI: 10.1056/NEJMoa2310168

Background: Biomarker changes that occur in the period between normal cognition and the diagnosis of sporadic Alzheimer's disease have not been extensively investigated in longitudinal studies.

Methods: We conducted a multicenter, nested case-control study of Alzheimer's disease biomarkers in cognitively normal participants who were enrolled in the China Cognition and Aging Study from January 2000 through December 2020. A subgroup of these participants underwent testing of cerebrospinal fluid (CSF), cognitive assessments, and brain imaging at 2-year-to-3-year intervals. A total of 648 participants in whom Alzheimer's disease developed were matched with 648 participants who had normal cognition, and the temporal trajectories of CSF biochemical marker concentrations, cognitive testing, and imaging were analyzed in the two groups.

Results: The median follow-up was 19.9 years (interquartile range, 19.5 to 20.2). CSF and imaging biomarkers in the Alzheimer's disease group diverged from those in the cognitively normal group at the following estimated number of years before diagnosis: amyloid-beta (Aβ) 42 , 18 years; the ratio of Aβ 42 to Aβ 40 , 14 years; phosphorylated tau 181, 11 years; total tau, 10 years; neurofilament light chain, 9 years; hippocampal volume, 8 years; and cognitive decline, 6 years. As cognitive impairment progressed, the changes in CSF biomarker levels in the Alzheimer's disease group initially accelerated and then slowed.

Conclusions: In this study involving Chinese participants during the 20 years preceding clinical diagnosis of sporadic Alzheimer's disease, we observed the time courses of CSF biomarkers, the times before diagnosis at which they diverged from the biomarkers from a matched group of participants who remained cognitively normal, and the temporal order in which the biomarkers became abnormal. (Funded by the Key Project of the National Natural Science Foundation of China and others; ClinicalTrials.gov number, NCT03653156 .).

Copyright © 2024 Massachusetts Medical Society.

Publication types

  • Clinical Study
  • Multicenter Study
  • Alzheimer Disease* / cerebrospinal fluid
  • Alzheimer Disease* / complications
  • Alzheimer Disease* / diagnosis
  • Alzheimer Disease* / diagnostic imaging
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Biomarkers* / cerebrospinal fluid
  • Case-Control Studies
  • Cognitive Dysfunction* / cerebrospinal fluid
  • Cognitive Dysfunction* / diagnostic imaging
  • Cognitive Dysfunction* / etiology
  • Follow-Up Studies
  • tau Proteins / cerebrospinal fluid
  • Amyloid beta-Peptides
  • tau Proteins

Associated data

  • ClinicalTrials.gov/NCT03653156

Grants and funding

  • 81261120571/NH/NIH HHS/United States

Alzheimer's Biomarkers Show Specific Changes 20 Years Before Diagnosis

— csf and imaging markers changed in a temporal sequence.

by Judy George , Deputy Managing Editor, MedPage Today February 21, 2024

A computer rendering of nerve cells affected by Alzheimer’s disease.

Biomarkers evolved in a temporal sequence over 20 years in people who developed Alzheimer's disease, a nested case-control study in China showed.

Over a median follow-up of 19.9 years, cerebrospinal fluid (CSF) and imaging biomarkers changed in a specific order, with differences seen in people who subsequently were diagnosed with sporadic Alzheimer's disease and people who remained cognitively normal, reported Jianping Jia, MD, PhD, of Capital Medical University in Beijing, and co-authors in the New England Journal of Medicine .

Among nearly 1,300 adults ages 45 to 65, temporal trajectories showed:

  • At 18 years before Alzheimer's diagnosis, CSF amyloid-beta 42 levels deviated between groups
  • At 14 years, the ratio of CSF amyloid-beta 42 to amyloid-beta 40 diverged
  • At 11 years, phosphorylated tau 181 CSF measures in the Alzheimer's group climbed
  • At 10 years, CSF total tau rose
  • At 9 years, CSF neurofilament light chain (NfL), a marker of axonal injury, increased
  • At 8 years, hippocampal atrophy on MRI differed between groups
  • At 6 years, cognitive decline was apparent in the Alzheimer's group based on Clinical Dementia Rating-Sum of Boxes (CDR-SB) assessments

As cognitive impairment progressed in the Alzheimer's disease group, CSF biomarker changes accelerated at first, and then slowed.

Biomarker changes in sporadic Alzheimer's disease were "similar in most respects to the temporal sequence of the appearance of differences of biomarkers in studies of autosomal dominant Alzheimer's disease, although the alterations in amyloid-beta 42 concentration became evident nearly a decade later in our study," Jia and colleagues noted.

The importance of this study "cannot be overstated," wrote Richard Mayeux, MD, of Columbia University in New York City, in an accompanying editorial . "Knowledge of the timing of these physiological events is critical to provide clinicians with useful starting points for prevention and therapeutic strategies," he observed.

The accuracy of a clinical diagnosis of Alzheimer's disease has been controversial, Mayeux noted.

"The National Alzheimer's Coordinating Center reported data from the National Institute on Aging Alzheimer's Disease Centers that indicated that the sensitivity of clinical diagnosis ranged from 70.9 to 87.3% and specificity varied from 44.3 to 70.8%, as compared with the reference standard of pathological diagnosis at autopsy," he pointed out. Biomarkers can provide "an opportunity to improve diagnostic accuracy in Alzheimer's disease and to establish objective diagnostic criteria."

Jia and co-authors used data from a nested study in the nationwide prospective China Cognition and Aging Study ( COAST ). Participants had CSF tests, cognitive assessments, and brain imaging at 2- to 3-year intervals. All were Han Chinese and were observed for more than 15 years, but not more than 20 years.

After propensity-score matching on age, sex, and education, 648 participants with Alzheimer's were successfully matched 1:1 with participants who remained cognitively normal at the last follow-up.

At baseline, participants had a mean age of about 61, and 50.6% were men. People eventually diagnosed with Alzheimer's were more likely than controls to carry an APOE4 allele (37.2% vs 20.4%).

Cognitive status was assessed at baseline and at each follow-up with three tests. Participants were considered to have no cognitive impairment if they scored 27 or higher on the Mini-Mental State Examination (MMSE, which ranges from 0 to 30, with higher scores representing better performance).

Scores of 12 or higher on the Logical Memory Test (LMT, which ranges from 0 to 25, with higher scores reflecting better memory) indicated normal baseline cognition. The third scale was the CDR-SB, which ranges from 0 to 18, with higher scores indicating greater impairment.

Baseline MMSE scores were about 29.5 in each group; LMT scores were 16.8, and CDR-SB scores were 0. At follow-up, cognitively normal was defined as consistently maintaining a CDR-SB score of 0.

In the Alzheimer's group, the progression of CSF markers appeared to accelerate initially, then peaked at an MMSE score of approximately 25 and an LMT score of approximately 11.

Because all participants were Han Chinese, the findings may not be generalizable to other populations, Jia and co-authors acknowledged. In addition, people with a familial history of Alzheimer's disease were excluded.

The study sample might not represent many older adults, the researchers noted. "The exclusion of participants with shorter follow-ups might have yielded a group resembling 'super-agers' -- persons endowed with higher education status, superior health status, and greater health awareness than persons not included in this study," they wrote.

Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more. Follow

Disclosures

This study was funded by the Key Project of the National Natural Science Foundation of China and others.

Jia reported relationships with Beijing municipal funding sources, the Beijing Natural Science Foundation, the Ministry of Science and Technology, and the National Natural Science Foundation of China. Co-authors reported no conflicts of interest.

Mayeux reported no conflicts of interest.

Primary Source

New England Journal of Medicine

Source Reference: Jia J, et al "Biomarker changes during 20 years preceding Alzheimer's disease" N Engl J Med 2024; DOI: 10.1056/NEJMoa2310168.

Secondary Source

Source Reference: Mayeux R "Alzheimer's disease biomarkers -- timing is everything" N Engl J Med 2024; DOI: 10.1056/NEJMe2400102.

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