APOE ε4, Alzheimer's Disease Pathology, Cerebrovascular Disease, and Cognitive Change Over the Years Prior to Death

The goal of this study was to examine the association of the APOE epsilon 4 allele with the late-life cognitive trajectory and test the hypothesis that the association of epsilon 4 with cognitive decline is explained by Alzheimer's disease (AD) neuropathology. Participants (N = 581) came from 2 longitudinal clinical-pathologic studies of aging and dementia, the Religious Orders Study (ROS) and the Memory and Aging Project (MAP). Longitudinal measures of cognition were derived from detailed annual neuropsychological testing. Uniform neuropathologic evaluations provided quantitative measures of AD pathology, chronic cerebral infarctions, and Lewy bodies. Participants with 1 or more copies of the epsilon 4 allele (epsilon 2/4 excluded) were considered epsilon 4 carriers. Random change point models were applied to examine the association of the epsilon 4 allele with onset of terminal decline as well as preterminal and terminal slopes. On average, the onset of terminal decline occurred around 3 years before death, and the rate of terminal decline was eightfold faster than the preterminal decline. The presence of the epsilon 4 allele was associated with an earlier onset of terminal decline and faster rates of decline before and after its onset. After adjusting for AD pathology, the epsilon 4 allele was no longer associated with onset of terminal decline or preterminal slope, and the association with terminal slope became marginal. The APOE epsilon 4 allele is an important determinant of late-life change in cognition, including terminal decline, and works primarily through AD pathology.