Moderation effects of APOE‐ε4 on marine omega‐3 fatty acids and its relation to change in cognitive function among community‐dwelling older adults

Abstract

AbstractBackgroundIn a recent trial, we observed no effect of omega‐3 fatty acids (omega‐3s) supplementation on cognitive decline. However, brain concentrations and metabolism of lipid molecules in response to omega‐3s may be regulated by apolipoprotein E (APOE)‐ε4 allele status. Further, while APOE‐ε4 is an established risk factor for Alzheimer disease, its association with cognitive decline is uncertain, especially in more diverse samples. The few randomized clinical trials (RCTs) addressing the moderation of effects of omega‐3s on cognitive decline by APOE‐ε4 have yielded inconsistent findings. Thus, we examined moderation by APOE‐ε4 on effects of omega‐3s vs. placebo for global and domain‐specific cognitive change over 2 years in a well‐characterized, diverse sample of older adults.MethodsVITamin D and OmegA‐3 TriaL (VITAL) is a 2×2 factorial RCT of vitamin D3 (2000 IU/day) and/or omega‐3s (1 g/day including 460 mg of eicosapentaenoic acid and 380 mg of docosahexaenoic acid) for cardiovascular disease and cancer prevention. We included 743 VITAL in‐clinic sub‐cohort participants who completed all cognitive tests at baseline and had APOE genotype data. The primary outcome was change in global cognition (averaging z‐scores of 9 tests) over 2 years; episodic memory and executive function/attention were examined separately. We used multiplicative interaction terms in general linear models of response profiles to examine moderation by APOE‐ε4 carrier status on effects of omega‐3s vs. placebo for cognitive change outcomes over 2 years.ResultsThe mean age (standard deviation) of participants was 67.1 (5.3) years; 50.6% were females; 13.5% were from racial and/or ethnic minority backgrounds; and 24.9% were APOE‐ε4 allele carriers. Over 2 years, compared with APOE‐ε4 non‐carriers, APOE‐ε4 carriers had faster declines in global cognition and episodic memory but not in executive function/attention; e.g., the mean difference in change (95% confidence interval) for episodic memory comparing APOE‐ε4 carriers vs. non‐carriers was ‐0.18 (‐0.33 to ‐0.03). There were no significant interactions between APOE‐ε4 carrier status and randomization status (omega‐3s vs. placebo) on change in global, episodic memory, or executive function/attention scores.ConclusionAPOE‐ε4 significantly predicted cognitive decline but did not modify the effect of omega‐3s on global and domain‐specific cognitive change over 2 years.