Role of APOE ɛ4 and ɛ2 With Longitudinal Cognitive Decline Among Those With Exceptional Longevity: The LifeAfter90 Study.

Abstract

Background and objectives: 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+.

Methods: 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.

Results: 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.

Discussion: After accounting for the competing risk of death, the negative consequences of ɛ4 on EF decline extend to those with exceptional longevity.