Abstract
ObjectiveTo examine whether genetic variation affecting the expression or function of lipid‐lowering drug targets is associated with Alzheimer disease (AD) risk, to evaluate the potential impact of long‐term exposure to corresponding therapeutics.MethodsWe conducted Mendelian randomization analyses using variants in genes that encode the protein targets of several approved lipid‐lowering drug classes: HMGCR (encoding the target for statins), PCSK9 (encoding the target for PCSK9 inhibitors, eg, evolocumab and alirocumab), NPC1L1 (encoding the target for ezetimibe), and APOB (encoding the target of mipomersen). Variants were weighted by associations with low‐density lipoprotein cholesterol (LDL‐C) using data from lipid genetics consortia (n up to 295,826). We meta‐analyzed Mendelian randomization estimates for regional variants weighted by LDL‐C on AD risk from 2 large samples (total n = 24,718 cases, 56,685 controls).ResultsModels for HMGCR, APOB, and NPC1L1 did not suggest that the use of related lipid‐lowering drug classes would affect AD risk. In contrast, genetically instrumented exposure to PCSK9 inhibitors was predicted to increase AD risk in both of the AD samples (combined odds ratio per standard deviation lower LDL‐C inducible by the drug target = 1.45, 95% confidence interval = 1.23–1.69). This risk increase was opposite to, although more modest than, the degree of protection from coronary artery disease predicted by these same methods for PCSK9 inhibition.InterpretationWe did not identify genetic support for the repurposing of statins, ezetimibe, or mipomersen for AD prevention. Notwithstanding caveats to this genetic evidence, pharmacovigilance for AD risk among users of PCSK9 inhibitors may be warranted. ANN NEUROL 2020;87:30–39
Highlights
In post hoc analyses to follow up on genetic analyses modeling proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition in relation to Alzheimer disease (AD) risk that were weighted by low-density lipoprotein cholesterol (LDL-C), we examined whether genetically indexed variation in circulating PCSK9 concentration is associated with AD risk
Findings were null in alternate Mendelian randomization” (MR) analyses using weighted median and MR Egger methods (Table 2), and these findings did not suggest any notable bias from directional pleiotropy or weak instruments in these models; for example, in analyses of the International Genomics of Alzheimer’s Project (IGAP) dataset, the MR Egger intercept test was 1.00 (p = 0.39), with I2gx of 98.7% in both datasets
Gene region models using the principal components (PC)-based approach for HMGCR, APOB, and NPC1-like intracellular cholesterol transporter 1 (NPC1L1) did not provide clear evidence to suggest that the use of the corresponding lipidlowering drug classes would affect AD risk
Summary
To examine whether genetic variation affecting the expression or function of lipid-lowering drug targets is associated with Alzheimer disease (AD) risk, to evaluate the potential impact of long-term exposure to corresponding therapeutics. Exposure and the use of more potent drugs.[7] In contrast, corresponding observational data on other lipid-lowering drug classes are scant and inconclusive.[7] Large randomized controlled trials (RCTs) may help to clarify the effects of dyslipidemia treatments on AD incidence without confounding, but such evidence is limited,[8] and the slowly evolving pathogenesis of AD (over at least 1 decade)[9,10] means it is ill-suited as an endpoint in trials of lipidlowering drugs with relatively short periods of intervention and follow-up (typically 2–5 years) Genetic epidemiology provides another means to address these questions. We examined whether AD risk is influenced by variation in the genes encoding the targets of a range of medications that are currently licensed and recommended for the treatment of primary or familial hypercholesterolemia to prevent coronary heart disease
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