APOE encodes a
cholesterol transporter, and the ε4 allele is associated with higher circulating
cholesterol levels, ß-
amyloid burden, and risk of
Alzheimer's disease. Prior studies demonstrated no significant differences in objective or subjective cognitive function for patients receiving the PCSK9 inhibitor
evolocumab vs. placebo added to
statin therapy. There is some evidence that
cholesterol-lowering medications may confer greater cognitive benefits in
APOE ε4 carriers. Thus, the purpose of this study was to determine whether
APOE genotype moderates the relationships between
evolocumab use and cognitive function.
APOE-genotyped patients (N = 13,481; 28% ε4 carriers) from FOURIER, a randomized, placebo-controlled trial of
evolocumab added to
statin therapy in patients with stable atherosclerotic
cardiovascular disease followed for a median of 2.2 years, completed the Everyday Cognition Scale (ECog) to self-report cognitive changes from the end of the trial compared to its beginning; a subset (N = 835) underwent objective cognitive testing using the Cambridge Neuropsychological Test Automated Battery as part of the EBBINGHAUS trial. There was a dose-dependent relationship between
APOE ε4 genotype and patient-reported memory decline on the ECog in the placebo arm (p = .003 for trend across genotypes; ε4/ε4 carriers vs. non-carriers: OR = 1.46, 95% CI [1.03, 2.08]) but not in the
evolocumab arm (p = .50, OR = 1.18, 95% CI [.83,1.66]). However, the genotype by treatment interaction was not significant (
p = .30). In the subset of participants who underwent objective cognitive testing with the CANTAB,
APOE genotype did not significantly modify the relationship between treatment arm and CANTAB performance after adjustment for demographic and medical covariates, (p's>.05). Although analyses were limited by the low population frequency of the ε4/ε4 genotype, this supports the cognitive safety of
evolocumab among ε4 carriers, guiding future research on possible benefits of
cholesterol-lowering medications in people at genetic risk for
Alzheimer's disease.