Lipid lowering and Alzheimer disease risk: A mendelian randomization study

Abstract

Objective: 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.

Methods: We 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).

Results: Models 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.

Interpretation: We 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.

Figure 1

Study overview. Black lines depict an illustrative gene region, with raised boxes showing exons. Wedges represent the presence of specific genetic variants (single nucleotide polymorphisms [SNPs]) measured throughout the gene. Different patterns of the wedges illustrate the combination of sources of low‐density lipoprotein cholesterol (LDL‐C) association statistics across variants from 1 of 3 LDL‐C genome‐wide association studies (GWASs; second and third panels). The pairing of wedges above and below the gene outline in panel 4 depicts the harmonization of appended LDL‐C statistics with corresponding estimates of Alzheimer disease (AD) risk for each variant within the 2 AD datasets separately. The varying number of wedges present across each dataset represents the differences in densities of SNPs that were genotyped or imputed in the data. GLGC = Global Lipid Genetics Consortium; IGAP = International Genomics of Alzheimer's Project; PGC = Psychiatric Genomics Consortium.

Figure 2

Meta‐analysis of Mendelian randomization estimates for Alzheimer disease (AD) risk according to a lifelong reduction in circulating low‐density lipoprotein cholesterol (LDL‐C) and exposure to the modulation of several related drug targets (n = 24,718 cases, 56,685 controls). The first group of results shows estimates for the effect of a general, long‐term reduction of LDL‐C (achievable by any means) on AD risk. The second to fifth group labels are representative of genetic variation at gene regions (HMGCR, PCSK9, APOB, and NPC1L1) that predict the effects of specific therapeutic target modulation, followed by example drug classes that affect these targets. CI = confidence interval; IGAP = International Genomics of Alzheimer's Project; OR = odds ratio; PGC = Psychiatric Genomics Consortium; SD = standard deviation; SNP = single nucleotide polymorphism.

Figure 3

Mendelian randomization estimates for the effects of exposure to drug target modulation on coronary artery disease (CAD) and type 2 diabetes mellitus (T2D). Results were produced using variants within gene regions (±1 kilobase flanks) and the principal components–based method, as per analyses for the Alzheimer disease results presented in Figure 1. Sample sizes: CAD, n = 22,233 cases, 64,762 controls; T2D, n = 12,171 cases, 56,862 controls. CI = confidence interval; LDL‐C = low‐density lipoprotein cholesterol; OR = odds ratio; SD = standard deviation; SNP = single nucleotide polymorphism.