APOE ε2 is associated with intact cognition but increased Alzheimer pathology in the oldest old
Open accessAbstract
BACKGROUND: Many studies have examined the role of APOE genotype in the development of dementia, specifically Alzheimer disease (AD). The APOE epsilon4 allele (APOE4) is a risk factor for both clinical and neuropathologic AD whereas the APOE epsilon2 allele (APOE2) seems to be protective. This would predict, even with advanced age, that APOE2 carriers would be less likely to have dementia and less likely to meet pathologic criteria for AD. METHODS: The first 85 genotyped participants from The 90+ Study to come to autopsy were included. All-cause dementia (using DSM-IV criteria) and AD (using National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria) diagnoses were made by consensus conference using all available information including neuropsychological testing, neurologic examination, and medical records. Neuropathologic examination included Braak and Braak staging for plaques and tangles and diagnosis of neuropathologic AD using National Institute on Aging-Reagan criteria. RESULTS: Across all genotypes, 58.5% of subjects were diagnosed with clinical dementia (81% of dementia was AD) and 50.0% met neuropathologic criteria for AD. Compared to those with an APOE epsilon3/epsilon3 genotype (APOE3/3), APOE4 carriers were more likely to be diagnosed with dementia (odds ratio [OR] = 12.2, 95% confidence interval [CI] = 1.5-102.0), whereas APOE2 carriers were not (OR = 0.3, 95% CI = 0.1-1.3). Surprisingly, both APOE4 (OR = 4.6, 95% CI = 1.3-16.5) and APOE2 (OR = 7.8, 95% CI = 1.5-40.2) carriers were more likely to meet neuropathologic criteria for AD than those with APOE3/3 genotype. CONCLUSIONS: In the oldest old, the presence of the APOE epsilon2 allele (APOE2) was associated with a somewhat reduced risk of dementia, but paradoxically was associated with increased Alzheimer disease (AD) neuropathology. Therefore, oldest old APOE2 carriers may have some mechanism that contributes to the maintenance of cognition independently of the formation of AD pathology.
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APOE2-induced deposition of diffuse plaques is novel in a mouse model and consistent with previous work by Dr. C. Kawas and co-workers.
“This APOE2induced deposition of diffuse plaques is novel in a mouse model and consistent with the previous work by Dr. C. Kawas and co-workers (54,55) who report that increased diffuse plaques are associated with APOE2 in cognitively normal subjects compared with compact plaques in APOE4 AD patients from the oldest of the old study.”
From APOE4-specific Changes in Aβ Accumulation in a New Transgenic Mouse Model of Alzheimer Disease (2012) · cites this paper as [54]
The Results (page unavailable) report a trend toward more diffuse plaques in oldest-old APOE2 carriers versus APOE3/3 carriers, and greater plaque pathology in non-demented APOE2 carriers. They do not establish increased diffuse plaques specifically in cognitively normal APOE2 subjects or the claimed contrast with compact plaques in APOE4 Alzheimer’s patients. The mouse-model novelty is the citing authors’ own finding, not a claim attributed to this source. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIt remains unclear whether apoE2 exerts its protective effect through modulating Aβ aggregation or an alternative mechanism that is independent of amyloid plaque formation.
“It remains unclear whether apoE2 exerts its protective effect through modulating Aβ aggregation or an alternative mechanism that is independent of amyloid plaque formation (Berlau et al., 2009).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Berlau et al., 2009
Many with plaques will remain asymptomatic for years or even decades, and perhaps some will never develop symptoms.
“After all, many with plaques will remain asymptomatic for years or even decades, and perhaps some will never develop symptoms [241].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [241]
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- Authors
- Berlau, D. J., Corrada, M. M., Head, E., & Kawas, C. H.
- Affiliations
- University of California, Irvine (US)
- From the Institute of Brain Aging and Dementia (D.J.B., M.M.C., E.H., C.H.K.) and Departments of Neurology (M.M.C., E.H., C.H.K.) and Neurobiology & Behavior (C.H.K.), University of California, Irvine.
- Venue
- Neurology
- Published
- 2009-03-03
- Volume
- 72
- Issue
- 9
- Pages
- 829-834
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- PMC
- PMC2667799
- OpenAlex
- W2092189536
- Cited by
- 185
- References
- 43
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 6 · 2023: 2 · 2022: 8 · 2021: 15 · 2020: 35 · 2019: 10 · 2018: 9 · 2017: 10 · 2016: 9 · 2015: 9 · 2014: 7 · 2013: 10 · 2012: 13
- FWCI
- 8.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Institute on Aging (R01 AG21055, R01AG021055, P50AG016573, T32AG000096)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Complementary and alternative medicine › Medicinal Plants and Neuroprotection
- Keywords
- APOE ε2, APOE ε4, APOE genotype, Alzheimer's disease, dementia, oldest old, cognitive function, neuropathology, amyloid plaques, neurofibrillary tangles, Braak staging, genetic risk factors
- MeSH terms
- Age Factors, Aged, Aged, 80 and over, Alzheimer Disease, Brain, Cognition, Female, Humans, Longitudinal Studies, Male, Neurons, Prospective Studies, Apolipoprotein E2
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