APOE ε4 and Accelerated Cognitive Decline Among Cognitively Healthy Middle-Aged and Older Adults.

Importance: Alzheimer disease (AD) pathology may begin decades before symptoms. Genetic factors, such as APOE ε4 carrier status and polygenic risk scores (PRS), influence AD risk, but their roles in cognitive decline among Asian populations remain unclear. Objective: To evaluate whether APOE ε4 carrier status and a non-APOE polygenic risk score (PRS_ADnapoe) are associated with age-related cognitive decline in community-dwelling older adults in Taiwan. Design, Setting, and Participants: This prospective cohort study used data from 2 assessment waves of the Healthy Aging Longitudinal Study in Taiwan, spanning 2009 to 2019. Participants were aged 55 years and older and had both genetic data and Mini-Mental State Examination (MMSE) scores. Data analyses were conducted from August to December 2025. Exposures: APOE ε4 carrier status (noncarrier, heterozygote, homozygote) and PRS_ADnapoe score, derived from genome-wide association summary statistics excluding APOE variants. Main Outcomes and Measures: The primary outcome was change in MMSE scores, which were assessed cross-sectionally and longitudinally, modeled with mixed-effects regression accounting for age-related effects and covariates including sex, education, smoking, and population structure. Results: Among 4392 participants (mean [SD] age, 68.2 [7.8] years; 2359 [53.7%] women), 723 (16.5%) were APOE ε4 heterozygotes and 33 (0.8%) were APOE ε4 homozygotes. Over a mean (SD) follow-up of 6.3 (0.9) years, the mean (SD) annual MMSE decline was -0.2 (0.5). APOE ε4 carriage was associated with a significantly steeper quadratic age-associated decline in MMSE scores compared with noncarriers (estimate, -0.005; SE, 0.001; P = .001). This association was strongest among homozygotes (estimate, -0.017; SE, 0.008; P = .03), with MMSE trajectories diverging after approximately age 70 years. In contrast, PRS_ADnapoe scores were not associated with MMSE decline. Sensitivity analyses restricted to participants with 2-wave data and adjusted with inverse probability of censoring weighting confirmed these findings. Conclusions and Relevance: In this cohort study of middle-aged and older adults in Taiwan, APOE ε4 carriage, particularly homozygosity, was associated with accelerated age-related cognitive decline detectable after age 70 years, whereas non-APOE polygenic risk was not associated with cognitive decline over the current follow-up. These results highlight the potential utility of early genetic risk awareness and support consideration of targeted preventive strategies for APOE ε4 carriers.