APOE epsilon2 is associated with intact cognition but increased Alzheimer pathology in the oldest old
Berlau DJ, Corrada MM, Head E, Kawas CH.. Neurology, 2009-03-01
Topic: Amyloid, tau and blood-test diagnosis
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.
Key findings
- 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).
- 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.
Why it matters
In 85 people aged 90 and older who came to autopsy, APOE epsilon 4 carriers were more likely to be diagnosed with dementia, while APOE epsilon 2 carriers were not. However, APOE epsilon 2 carriers were more likely to meet neuropathologic criteria for Alzheimer's disease despite having intact cognition, suggesting the relationship between this allele, cognition and brain pathology is complex in the oldest old.
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Study details
- Effect size58.5%; 50.0%; OR = 0.3
- Evidence strengthLow
How this study scored 50/100
Published in a leading specialty journal. Scored zero for study design, sample size, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Neurology) |
| Journal's citation record | 4 / 4 | Neurology: journal h-index 525 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2009 — within 20 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 3 / 3 | Effect reported with a statistic (interval, p-value, ratio or similar) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 184 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 9.7 citations a year over 19 year(s) since 2009 |
| Impact for its field and year | 3 / 6 | Cited 8.0× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 13 other studies in this library |
| Still being cited | 2 / 4 | Cited 17 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Claudia H. Kawas: h-index 85 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | University of California, Irvine: institution h-index 1,195 (OpenAlex) |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 19255410) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 50 / 100 | — |
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Read the original
- DOI: 10.1212/01.wnl.0000343853.00346.a4
- PubMed: 19255410
- Original source →
- Free full text: PubMed Central →
Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Berlau, D. J., Corrada, M. M., Head, E., & Kawas, C. H. (2009). APOE epsilon2 is associated with intact cognition but increased Alzheimer pathology in the oldest old. Neurology. https://doi.org/10.1212/01.wnl.0000343853.00346.a4
Vancouver
Berlau DJ, Corrada MM, Head E, Kawas CH. APOE epsilon2 is associated with intact cognition but increased Alzheimer pathology in the oldest old. Neurology. 2009. doi:10.1212/01.wnl.0000343853.00346.a4. PMID: 19255410.
BibTeX
@article{berlau2009-19255410,
author = {Berlau, D. J. and Corrada, M. M. and Head, E. and Kawas, C. H.},
title = {{APOE epsilon2 is associated with intact cognition but increased Alzheimer pathology in the oldest old}},
journal = {Neurology},
year = {2009},
doi = {10.1212/01.wnl.0000343853.00346.a4},
pmid = {19255410},
url = {https://doi.org/10.1212/01.wnl.0000343853.00346.a4}
}
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