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 epsilon 2 epsilon 4 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), epsilon 2 epsilon 4 accounted for 2.5%, epsilon 2 epsilon 2 accounted for 0.4%, epsilon 2 epsilon 3 accounted for 11.0%, epsilon 4 epsilon 4 accounted for 4.4%, epsilon 3 epsilon 4 accounted for 27.3%, and epsilon 3 epsilon 3 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 epsilon 3 epsilon 3 carriers, epsilon 2 epsilon 4 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 epsilon 3 epsilon 3 carriers, epsilon 2 epsilon 4 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 epsilon 2 epsilon 4 genotype is associated with the increased risk of AD and MCI in non-Latino whites.