After accounting for the competing risk of death, the negative consequences of APOE ε4 on executive function decline extend to those with exceptional longevity, while ε2 carriers showed slower verbal episodic memory decline.
APOE ε4 carriers aged 90+ had faster decline in executive function compared to non-ε4 carriers.
APOE ε4 carriers did not show substantially different decline in verbal episodic memory or semantic memory compared to non-ε4 carriers.
APOE ε2 carriers aged 90+ had slower decline in verbal episodic memory compared to non-ε2 carriers.
APOE ε2 carriers showed similar decline in executive function and semantic memory compared to non-ε2 carriers.
Neither ε4 nor ε2 carrier status was substantially associated with mortality hazard in this 90+ population.
The LifeAfter90 study cohort was a multiethnic sample of 445 individuals aged 90 and older with a mean baseline age of 93 years.
This research suggests that even among people who live to age 90 and beyond — a group sometimes thought to have 'survived' typical Alzheimer's risk — carrying the APOE ε4 gene variant still has measurable negative effects on cognitive health. Specifically, people aged 90+ who carried the ε4 variant showed faster decline in executive function (the ability to plan, focus, and manage tasks) compared to non-carriers, even after accounting for the fact that some participants died during the study. Interestingly, ε4 did not appear to affect verbal memory or semantic memory in this age group, suggesting its impact at extreme old age may be more specific than at younger ages. On the protective side, carrying the APOE ε2 variant — generally considered beneficial for brain health — was associated with slower decline in verbal episodic memory (the ability to recall personally experienced events) among those aged 90+. However, ε2 did not appear to significantly protect executive function or semantic memory in this age group. Neither genetic variant was strongly linked to differences in survival during the study period. This research is notable because it studied a diverse, multiethnic group of 445 people aged 90 to 104, a population that is rarely included in Alzheimer's research. The findings suggest that genetic factors influencing cognitive aging do not simply 'turn off' at extreme old age, though their effects may shift in nature. Understanding how these genes affect the very old could help researchers better target interventions for an increasingly large segment of the population.
Colbeth H, Posis A, Rizvi B, Decarli C, Glymour M, George K, et al.. (2026). Role of APOE ɛ4 and ɛ2 With Longitudinal Cognitive Decline Among Those With Exceptional Longevity: The LifeAfter90 Study.. Neurology. https://doi.org/10.1212/WNL.0000000000218596