No association between APOE genotype and lipid lowering with cognitive function in a randomized controlled trial of evolocumab.

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.

Déclaration de conflit d'intérêts

The FOURIER and EBBINGHAUS trials were supported by Amgen. No funds were provided for writing this manuscript. This does not alter our adherence to PLOS ONE policies on data sharing and materials. Dr. Giugliano reports research grant support through Brigham and Women’s Hospital from Amgen, Anthos, and Daiichi Sankyo; honoraria for continuing medical education lectures from Amgen, Daiichi Sankyo, Dr Reddy’s Laboratories, Menarini, Merck, Pfizer, SAJA, and Servier; honoraria for consulting from Amarin, Amgen; AstraZeneca, Bristol-Myers Squibb, CVS Caremark, Daiichi Sankyo, Esperion, GlaxoSmithKline, Janssen, Merck, and Pfizer. Dr Sabatine reports honoraria for consulting from Althera, Amgen, Anthos Therapeutics, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, DalCor, Dr Reddy’s Laboratories, Dyrnamix, Esperion, IFM Therapeutics, Intarcia, Janssen Research and Development, The Medicines Company, MedImmune, Merck, and Novartis; research grant support through Brigham and Women’s Hospital from Amgen, AstraZeneca, Bayer, Daiichi Sankyo, Eisai, Intarcia, Janssen Research and Development, The Medicines Company, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, and Takeda. Prof. Mach was a member of the Steering Committee of the FOURIER trial and of the Executive Committee of the EBBINGHAUS trial. Dr. Ott reports honoraria for consulting from Amgen, Biogen, and Corium and research grant support from Biogen, Eli Lilly, and AbbVie. Drs Giugliano, Sabatine, Ms Guo are members of the TIMI Study Group, which has also received research grant support through Brigham and Women’s Hospital from Abbott, Anthos, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Daiichi Sankyo, Eisai, Intarcia, The Medicines Company, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Roche, and Zora Biosciences. This does not alter our adherence to PLOS ONE policies on data sharing and materials.