Effects of APOE on Cognitive Aging in Community-Dwelling Older Adults

Objective: The apolipoprotein E (APOE) gene is an established risk factor for sporadic Alzheimer's disease, with elevated risk for epsilon 4-carriers and reduced risk for epsilon 2-carriers. However, it is unclear whether APOE modifies risk for cognitive decline in normal aging. The objective of this study was to determine whether epsilon 2 and epsilon 4 are associated with rates of normal cognitive aging, and whether associations of epsilon 4 with cognitive decline are modified by sex, education or health behaviors (exercise, alcohol consumption, smoking). Method: A community-based sample of 1,393 older adults were genotyped for APOE and underwent cognitive assessment up to seven times over a maximum of period of 27 years. Results: epsilon 2-carriers showed slower executive function decline with age relative to epsilon 3 homozygotes or epsilon 4-carriers, whereas epsilon 4-carriers demonstrated more rapid executive function and verbal fluency decline. Accelerated executive function decline was particularly pronounced in epsilon 4-carriers with lower education. After excluding individuals with cognitive impairment, faster executive function decline was still apparent in epsilon 4-carriers, and the effect of epsilon 4 on episodic memory interacted with alcohol consumption, such that only epsilon 4-carriers who did not drink showed more rapid memory decline than epsilon 4 noncarriers. The influence of epsilon 4 on cognitive aging did not differ by sex, nor was it modified by smoking or exercise. Conclusions: These findings indicate that the epsilon 2 and epsilon 4 alleles have differential effects on cognitive aging, and that negative effects of epsilon 4 may be partly mitigated by behavioral choices.