APOEε2 is associated with milder clinical and pathological Alzheimer disease
Serrano-Pozo A, Qian J, Monsell SE, Betensky RA, Hyman BT.. Annals of neurology, 2015-06-01
Topic: Amyloid, tau and blood-test diagnosis
Objective The Alzheimer disease (AD) APOEε4 risk allele associates with an earlier age at onset and increased amyloid-β deposition, whereas the protective APOEε2 allele delays the onset and appears to prevent amyloid-β deposition. Yet the clinical and pathological effects of APOEε2 remain uncertain because of its relative rarity. We investigated the effects of APOEε2 and ε4 alleles on AD pathology and cognition in a large US data set of well-characterized AD patients. Methods We studied individuals from the National Alzheimer's Coordinating Center autopsy cohort across the entire clinicopathological continuum of AD. Multivariate models were built to examine the associations between APOE alleles and AD neuropathological changes, using the APOEε3/ε3 group as comparator. Mediation analysis was used to estimate the direct and indirect effects of APOE alleles on AD pathology and cognition (Clinical Dementia Rating Sum of Boxes and Mini-Mental State Examination). Results Compared to APOEε3/ε3, APOEε2 is independently associated with lower Braak neurofibrillary tangle (NFT) stages and possibly fewer neuritic plaques, but has no direct effect on cerebral amyloid angiopathy (CAA) severity, whereas APOEε4 is associated with more neuritic plaques and CAA, but has no independent effect on Braak NFT stage. Unadjusted analyses showed marked differences among APOE genotypes with respect to cognitive performance (ε2 > ε3 > ε4). Mediation analysis suggests that this is largely explained through effects on pathology. Interpretation Even when adjusted for age at onset, symptom duration, and other demographic variables, APOEε2 is associated with milder AD pathology and less severe antemortem cognitive impairment compared to APOEε3 and ε4 alleles, suggesting a relative neuroprotective effect of APOEε2 in AD.
Key findings
- Results Compared to APOEε3/ε3, APOEε2 is independently associated with lower Braak neurofibrillary tangle (NFT) stages and possibly fewer neuritic plaques, but has no direct effect on cerebral amyloid angiopathy (CAA) severity, whereas APOEε4 is associated with more neuritic plaques and CAA, but has no independent effect on Braak NFT stage.
- Mediation analysis suggests that this is largely explained through effects on pathology.
- Interpretation Even when adjusted for age at onset, symptom duration, and other demographic variables, APOEε2 is associated with milder AD pathology and less severe antemortem cognitive impairment compared to APOEε3 and ε4 alleles, suggesting a relative neuroprotective effect of APOEε2 in AD.
Why it matters
In this autopsy cohort study, the APOE ε2 allele was independently associated with lower Braak neurofibrillary tangle stages and possibly fewer neuritic plaques, while APOE ε4 was associated with more neuritic plaques and cerebral amyloid angiopathy. These findings help explain genetic effects on Alzheimer's disease pathology but do not provide a treatment, cure, or prevention.
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Study details
- Evidence strengthModerate
How this study scored 55/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported, 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 (Annals of neurology) |
| Journal's citation record | 3 / 4 | Annals of Neurology: journal h-index 437 (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 | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2015 — 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 | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| 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 176 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 13.5 citations a year over 13 year(s) since 2015 |
| Impact for its field and year | 4 / 6 | Cited 9.1× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 14 other studies in this library |
| Still being cited | 3 / 4 | Cited 52 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Bradley T. Hyman: h-index 190 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | University of Washington: institution h-index 3,540 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 6 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 25623662) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 55 / 100 | — |
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APA 7th
Serrano-Pozo, A., Qian, J., Monsell, S. E., Betensky, R. A., & Hyman, B. T. (2015). APOEε2 is associated with milder clinical and pathological Alzheimer disease. Annals of neurology. https://doi.org/10.1002/ana.24369
Vancouver
Serrano-Pozo A, Qian J, Monsell SE, Betensky RA, Hyman BT. APOEε2 is associated with milder clinical and pathological Alzheimer disease. Annals of neurology. 2015. doi:10.1002/ana.24369. PMID: 25623662.
BibTeX
@article{serranopozo2015-25623662,
author = {Serrano-Pozo, A. and Qian, J. and Monsell, S. E. and Betensky, R. A. and Hyman, B. T.},
title = {{APOEε2 is associated with milder clinical and pathological Alzheimer disease}},
journal = {Annals of neurology},
year = {2015},
doi = {10.1002/ana.24369},
pmid = {25623662},
url = {https://doi.org/10.1002/ana.24369}
}
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