The Effect of the APOE ε2ε4 Genotype on the Development of Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI) in Non‐Latino Whites

OBJECTIVES: To examine the associations of APOE ε2ε4 with the development of Alzheimer's disease (AD) and mild cognitive impairment (MCI) in non-Latino whites. DESIGN: Prospective longitudinal cohort study. SETTING: Uniform Data Set from the National Alzheimer's Coordinating Center (NACC) between 2005 and August 2018 (data freeze in September 2018). PARTICIPANTS: Participants who were non-Latino white, had an APOE genotype available, first visit with dementia free for AD cohort and both dementia and MCI free for MCI cohort, and had a minimum of one follow-up visit (n = 11 871 for AD cohort, and n = 8305 for MCI cohort). MEASUREMENTS: The incidences of AD and MCI were determined based on consensus meetings at each Alzheimer's disease center. We used NACC-derived variables to define individuals experiencing incidents of AD and MCI at the initial visit as well as the follow-up visits. RESULTS: Among participants in the AD cohort (N = 11 871), ε2ε4 accounted for 2.5%, ε2ε2 accounted for 0.4%, ε2ε3 accounted for 11.0%, ε4ε4 accounted for 4.4%, ε3ε4 accounted for 27.3%, and ε3ε3 accounted for 54.4%. Over an average of 4.6 years follow-up, 1857 (15.6%) developed AD dementia, with the range from 6.0% to 35.2% across the six groups. Compared to ε3ε3 carriers, ε2ε4 carriers exhibited an increased risk of incident AD (18.4% vs 11.7%; adjusted hazard ratio [aHR] = 1.74; 95% confidence interval [CI] = 1.32-2.30; P < .0001). Among participants in the MCI cohort (N = 8305), the average follow-up was 4.7 years, and 1912 (23.0%) developed MCI, with the range from 20.4% to 33.9% across the six groups. Compared to ε3ε3 carriers, ε2ε4 carriers exhibited an increased risk of incident MCI (27.5% vs 21.5%; aHR = 1.52; 95% CI = 1.15-1.99; P = .003). CONCLUSIONS: The APOE ε2ε4 genotype is associated with the increased risk of AD and MCI in non-Latino whites. J Am Geriatr Soc 68:1044-1049, 2020.