Authors
Hilary L Colbeth, Alexander Ivan B Posis, Batool Mahboob Rizvi, Charles S Decarli, M Maria Glymour, Kristen M George, Maria M Corrada, Paola Gilsanz, Rachel A Whitmer
Published in
Neurology. Volume 107. Issue 9. Pages e218596. Nov 10, 2026. Epub Oct 16, 2026.
Abstract
APOE ɛ4 is the strongest genetic risk factor for late-onset Alzheimer disease, while ɛ2 is associated with decreased risk. However, it is unclear how these genotypes relate to cognitive decline among those aged older than 90+. We examined associations of ɛ4 and ɛ2 with longitudinal change in 3 cognitive domains among individuals aged 90+.
LifeAfter90 is an ongoing longitudinal multiethnic cohort study of those aged 90+. APOE genotyping was conducted using DNA extracted from saliva. Two dichotomous exposures were defined as ɛ4 carriers (ɛ2/ɛ4, ɛ3/ɛ4, or ɛ4/ɛ4 genotypes) vs non-ɛ4-carriers with no ɛ4 allele and ɛ2 carriers (ɛ2/2, ɛ2/3 genotypes) vs non-ɛ2-carriers (ɛ3/ɛ3, ɛ2/ɛ4, ɛ3/ɛ4, or ɛ4/ɛ4). Executive function (EF), semantic memory (SM), and verbal episodic memory (VEM) were measured every 6 months on up to 11 occasions using the Spanish and English Neuropsychological Scales. Time to all-cause mortality was calculated from baseline to death. We fit linear mixed-effects (LME) models and joint models (LME and Cox proportional hazard submodels) to account for the competing risk of death. Models adjusted for age and sex.
We evaluated 445 participants (mean age at baseline 93 years, SD 2.31, range 90-104; 59% female). In total, 20% were ɛ4 carriers, 15% were ɛ2 carriers, and 54% died during follow-up. The ethnoracial composition was 21% African American/Black, 22% as Asian, 16% as Hispanic/Latinx, 9% as multiracial/other, and 32% as White. The mean follow-up time was 3.9 years (SD 1.63, range 0.68-6.67). Neither ɛ4 nor ɛ2 carriers averaged substantially greater or lesser mortality hazard than noncarriers. In joint models, ɛ4 carriers had faster decline in EF (β = -0.07, 95% CI -0.12 to -0.02), but similar decline in VEM (β = -0.01, 95% CI -0.08 to 0.05) and SM (β = -0.03; 95% CI -0.08 to 0.02). APOE ɛ2 carriers had similar decline in EF (β = 0.01, 95% CI -0.05 to 0.08) and SM (β = 0.01, 95% CI -0.05 to 0.08) but slower decline in VEM (β = 0.07, 95% CI 0.00-0.15) compared with noncarriers. Longitudinal results were similar for LME and joint models.
After accounting for the competing risk of death, the negative consequences of ɛ4 on EF decline extend to those with exceptional longevity.
PMID:
42886871
Bibliographic data and abstract were imported from PubMed on 17 Oct 2026.
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