APOE epsilon 2 epsilon 4 genotype, incident AD and MCI, cognitive decline, and AD pathology in older adults

Objective To examine the association of the APOE epsilon 2 epsilon 4 genotype with incident Alzheimer disease (AD), mild cognitive impairment (MCI), cognitive decline, and AD pathology in older adults. Methods We used data from 2,151 older adults of European ancestry who were free of dementia at baseline and underwent structured annual clinical evaluation in a longitudinal study for incident AD and MCI, and cognitive decline. Postmortem examination in decedents documented pathologic AD and quantified ss-amyloid and neurofibrillary tangles. Participants were stratified into 4 groups based on APOE genotyping: epsilon 2 epsilon 4, epsilon 4 (epsilon 4 epsilon 4, epsilon 4 epsilon 3), epsilon 2 (epsilon 2 epsilon 2, epsilon 2 epsilon 3), with epsilon 3 epsilon 3 carriers serving as the reference group. We used Cox proportional hazards models to examine the association of APOE genotype with incident AD and MCI. Linear mixed-effect models were used to examine the association with cognitive decline. Logistic and linear regression models were used to examine AD pathology. All the models controlled for age, sex, and education. Results Of the 2,151 participants included in this study, epsilon 2 epsilon 4 accounted for 2.1%, epsilon 3/4 and 4/4 21.8%, epsilon 2/3 and 2/2 14.0%, and epsilon 3 epsilon 3 62.1%. We did not observe a difference in the risk of AD for epsilon 2 epsilon 4 compared to epsilon 3 epsilon 3. In cases without cognitive impairment at baseline, epsilon 2 epsilon 4 carriers had an increased risk of incident MCI (hazard ratio 2.13, 95% confidence interval 1.34-3.39, p = 0.002) and a faster rate of cognitive decline (estimate -0.047, SE 0.018, p = 0.008) compared to epsilon 3 epsilon 3 carriers. In decedents (n = 1,100), epsilon 2 epsilon 4 showed a 3-fold increased odds of pathologic AD and a higher ss-amyloid load than epsilon 3 epsilon 3. Conclusion APOE epsilon 2 epsilon 4 genotype in older adults is associated with risk of MCI, cognitive decline, and a greater burden of AD pathology, especially ss-amyloid