Context: Impairment of episodic memory is an early and defining feature of Alzheimer disease (AD). The apolipoprotein E (APOE) ε4 allele is known to influence risk of AD but it has been difficult to establish whether it affects episodic memory differently from other cognitive functions. Objective: To examine the association of ε4 with decline in different cognitive systems. Design: Longitudinal cohort study. Setting: More than 40 groups of Catholic clergy from across the United States. Participants: Older Catholic clergy members without clinical evidence of dementia at baseline underwent annual clinical evaluations for up to 6 years. Of 624 persons eligible for follow-up, 611 (98%) participated, of whom 161 (26%) had at least 1 ε4 allele. They completed an average of 5.5 evaluations (range, 2-7). Main Outcome Measures: Incident AD and annual rates of change in episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability. Results: The presence of ε4 was associated with risk of developing AD on follow-up (relative risk, 1.92; 95% confidence interval, 1.27-2.89). In a series of random effects models, ε4 was associated with impaired baseline function in episodic memory and visuospatial ability and with more rapid decline in all domains. The effect of ε4 on annual decline in episodic memory (>3-fold increase) was significantly stronger than its effect on decline in other cognitive systems (P<.01), and at baseline, its effect on episodic memory was marginally stronger than its effect on other cognitive domains (P=.06). Conclusion: The results suggest that the APOE ε4 allele influences risk of AD by a relatively selective effect on episodic memory.
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