Alzheimer’s disease is not “brain aging”: neuropathological, genetic, and epidemiological human studies
Open accessAbstract
Human studies are reviewed concerning whether "aging"-related mechanisms contribute to Alzheimer's disease (AD) pathogenesis. AD is defined by specific neuropathology: neuritic amyloid plaques and neocortical neurofibrillary tangles. AD pathology is driven by genetic factors related not to aging per se, but instead to the amyloid precursor protein (APP). In contrast to genes involved in APP-related mechanisms, there is no firm connection between genes implicated in human "accelerated aging" diseases (progerias) and AD. The epidemiology of AD in advanced age is highly relevant but deceptively challenging to address given the low autopsy rates in most countries. In extreme old age, brain diseases other than AD approximate AD prevalence while the impact of AD pathology appears to peak by age 95 and decline thereafter. Many distinct brain diseases other than AD afflict older human brains and contribute to cognitive impairment. Additional prevalent pathologies include cerebrovascular disease and hippocampal sclerosis, both high-morbidity brain diseases that appear to peak in incidence later than AD chronologically. Because of these common brain diseases of extreme old age, the epidemiology differs between clinical "dementia" and the subset of dementia cases with AD pathology. Additional aging-associated mechanisms for cognitive decline such as diabetes and synapse loss have been linked to AD and these hypotheses are discussed. Criteria are proposed to define an "aging-linked" disease, and AD fails all of these criteria. In conclusion, it may be most fruitful to focus attention on specific pathways involved in AD rather than attributing it to an inevitable consequence of aging.
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Research has shown that 15% to 30% of those diagnosed with Alzheimer's dementia during life do not have the brain changes of Alzheimer's disease but instead have brain changes of another cause of dementia.
“research has shown that 15% to 30% of those diagnosed with Alzheimer's dementia during life do not have the brain changes of Alzheimer's disease but instead have the brain changes of another cause of dementia”
From 2023 Alzheimer's disease facts and figures (2023) · cites this paper as [71]
The Introduction and definition of terms (page unavailable) says clinical and autopsy diagnoses do not always agree. The AD and dementia epidemiology section (page unavailable) describes cognitively impaired people who lack AD pathology and identifies other brain diseases that can cause dementia. It does not establish that 15%–30% of people diagnosed with Alzheimer’s dementia during life have another dementia pathology instead. (LLM, conf=0.84)
Experimental — accuracy not yet measuredFrom 10% to 30% of individuals clinically diagnosed as AD dementia by experts do not display AD neuropathologic changes at autopsy.
“From 10% to 30% of individuals clinically diagnosed as AD dementia by experts do not display AD neuropathologic changes at autopsy [50]”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [50]
The Introduction and definition of terms describes imperfect agreement between clinical diagnosis and autopsy findings. The section on AD pathology in persons past 90 years of age also discusses cognitively impaired people whose brains lack AD pathology at autopsy. Neither passage establishes the claimed 10%–30% rate among people diagnosed with AD dementia by experts. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn clinical-autopsy studies, diabetes was associated with cognitive impairment (and the clinical diagnosis of probable AD); however, the pathologic basis for this association was vascular brain injury and not Aβ plaques and neurofibrillary degeneration.
“In contrast, in clinical-autopsy studies, diabetes was associated with cognitive impairment (and the clinical diagnosis of probable AD); however, the pathologic basis for this association was vascular brain injury and not Aβ plaques and neurofibrillary degeneration [50,216].”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [50]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredAD neuropathologic change is documented in approximately 80% of cases with a traditional clinical diagnosis of "AD dementia".
“AD neuropathologic change is documented in approximately 80% of cases with a traditional clinical diagnosis of “AD dementia” (see Fig. 5 for an example of clinical misdiagnosis of “AD dementia”) [50–52,162,185,209–211].”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [50]
The Introduction and definition of terms (page unavailable) describes an imperfect correlation between clinical diagnosis and autopsy pathology. The AD and dementia epidemiology section (page unavailable) also says that some cognitively impaired people lack AD pathology, particularly in extreme old age. Neither passage establishes that AD neuropathologic change is found in approximately 80% of cases clinically diagnosed with AD dementia. (LLM, conf=0.78)
Experimental — accuracy not yet measuredThe risk of developing Alzheimer's dementia increases with inheriting one copy of the e4 form and increases further still with inheriting two copies of the e4 form, compared with inheriting only copies of the e2 or e3 forms.
“In general, the risk of developing Alzheimer's dementia increases with inheriting one copy of the e4 form and increases further still with inheriting two copies of the e4 form, compared with inheriting only copies of the e2 or e3 forms.”
From 2024 Alzheimer's disease facts and figures (2024) · cites this paper as [79]
The “AD genetic risk factors” section (page unavailable) identifies APOE ε4 as the strongest risk factor for late-onset Alzheimer’s disease. It does not state that two ε4 copies confer greater risk than one, or give the claimed comparison with ε2/ε3-only genotypes. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Both autopsy studies and clinical trials have found that 15% to 30% of individuals who meet the criteria for clinical Alzheimer's dementia based on symptoms did not have Alzheimer's-related brain changes.
“Both autopsy studies and clinical trials have found that 15% to 30% of individuals who meet the criteria for clinical Alzheimer's dementia based on symptoms did not have Alzheimer's‐related brain changes.”
From 2024 Alzheimer's disease facts and figures (2024) · cites this paper as [79]
The section ‘AD pathology in persons past 90 years of age’ (page unavailable) describes cognitively impaired people whose brains lack AD pathology at autopsy. But the paper does not establish that 15%–30% of people meeting clinical Alzheimer’s dementia criteria lack those changes, or report that clinical trials found that proportion. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPrevalence estimates of dementia due to Alzheimer's disease based on Alzheimer's brain changes as well as overt clinical dementia symptoms are likely to be lower than the 6.9 million figure reported.
“Prevalence estimates of dementia due to Alzheimer's disease based on Alzheimer's brain changes, as well as overt clinical dementia symptoms, are likely to be lower than the 6.9 million figure reported here.”
From 2024 Alzheimer's disease facts and figures (2024) · cites this paper as [79]
The Introduction defines definitive Alzheimer’s disease by both clinical dementia and characteristic brain pathology. The “AD pathology in persons past 90 years of age” section says dementia can increase in extreme old age without a corresponding increase in Alzheimer’s pathology, supporting the possibility that a pathology-based estimate would be lower. The paper does not estimate prevalence against the citing document’s 6.9 million figure or establish how much lower it would be. (LLM, conf=0.82)
Experimental — accuracy not yet measuredResearch has shown that 15% to 30% of those diagnosed with Alzheimer's dementia during life do not have the brain changes of Alzheimer's disease but instead have the brain changes of another cause of dementia.
“research has shown that 15% to 30% of those diagnosed with Alzheimer's dementia during life do not have the brain changes of Alzheimer's disease but instead have the brain changes of another cause of dementia”
From 2024 Alzheimer's disease facts and figures (2024) · cites this paper as [79]
The Introduction and definition of terms (page unavailable) says clinical expectations do not always match autopsy-proven pathology. The section on AD pathology in persons past 90 years of age (page unavailable) describes cognitively impaired people who lack AD pathology and discusses other brain diseases that contribute to dementia. The paper does not establish the claimed 15%–30% figure for people diagnosed with Alzheimer’s dementia during life. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAlzheimer's dementia is not a normal part of aging, and older age alone is not sufficient to cause Alzheimer's dementia.
“However, it is important to note that Alzheimer's dementia is not a normal part of aging, and older age alone is not sufficient to cause Alzheimer's dementia.71”
From 2023 Alzheimer's disease facts and figures (2023) · cites this paper as [71]
The prototypical multidomain amnestic dementia phenotype historically used to define probable AD does not 'rule in' AD pathologic change at autopsy.
“It is now well established that the prototypical multidomain amnestic dementia phenotype historically used to define probable AD [1] does not “rule in” AD pathologic change (which implies change from normal) at autopsy [50–52]”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [50]
The absence of the prototypical multidomain amnestic dementia syndrome does not 'rule out' AD pathologic change.
“and the absence of the syndrome does not “rule out” AD pathologic change.”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [50]
Having the e4 form of APOE increases one's risk of developing Alzheimer's dementia compared with having the e3 or e2 forms but does not guarantee that an individual will develop Alzheimer's dementia.
“Having the e4 form of APOE increases one's risk of developing Alzheimer's dementia compared with having the e3 or e2 forms but does not guarantee that an individual will develop Alzheimer's dementia.”
From 2024 Alzheimer's disease facts and figures (2024) · cites this paper as [79]
APOE-e4 has the strongest impact on risk of late-onset Alzheimer's dementia among the many genes that increase risk.
“Of the many genes that increase risk, APOE‐e4 has the strongest impact on risk of late‐onset Alzheimer's dementia.”
From 2024 Alzheimer's disease facts and figures (2024) · cites this paper as [79]
Alzheimer's dementia is not a normal part of aging, and older age alone is not sufficient to cause Alzheimer's dementia.
“However, it is important to note that Alzheimer's dementia is not a normal part of aging, and older age alone is not sufficient to cause Alzheimer's dementia.”
From 2024 Alzheimer's disease facts and figures (2024) · cites this paper as [79]
In the oldest old, the prevalence of concomitant non-AD brain diseases, including CVD and hippocampal sclerosis, begins to mimic the effects of AD pathologic diagnosis.
“Thus, in the oldest old, the prevalence of concomitant non-AD brain diseases, including CVD and hippocampal sclerosis, begins to mimic the effects of AD pathologic diagnosis (154, 221, 222).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [222]
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References 249 · Cited by 365
- Authors
- Nelson, P. T., Head, E., Schmitt, F. A., Davis, P. R., Neltner, J. H., Jicha, G. A., Abner, E. L., Smith, C. D., Van Eldik, L. J., Kryscio, R. J., & Scheff, S. W.
- Affiliations
- University of Kentucky (US)
- Corresponding author
- Nelson, Peter T.
- ORCID
- Venue
- Acta Neuropathologica
- Published
- 2011-04-24
- Volume
- 121
- Issue
- 5
- Pages
- 571-587
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC3179861
- OpenAlex
- W1975216966
- Cited by
- 365
- References
- 249
- Citations by year
- 2026: 14 · 2025: 19 · 2024: 42 · 2023: 19 · 2022: 25 · 2021: 36 · 2020: 28 · 2019: 27 · 2018: 26 · 2017: 22 · 2016: 16 · 2015: 20 · 2014: 25 · 2013: 24 · 2012: 16
- FWCI
- 2.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Acta Neuropathologica (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (P30AG028383, U01AG016976)
- National Institute of Neurological Disorders and Stroke (R01NS061933, K08NS050110)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HHSN275200900011C)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, brain aging, amyloid plaques, neurofibrillary tangles, amyloid precursor protein, Hutchinson-Gilford progeria syndrome, accelerated aging, oldest old, autopsy rates, cerebrovascular disease, hippocampal sclerosis, cognitive impairment, diabetes mellitus, synaptic loss, dementia
- MeSH terms
- Aged, Aged, 80 and over, Aging, Alzheimer Disease, Brain, Humans, Neurons, Risk Factors, Genetic Predisposition to Disease
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