Lipid lowering and Alzheimer disease risk: A mendelian randomization study

• Published in: Annals of neurology 2020-01, Vol.87 (1), p.30-39
• Main Authors: Williams, Dylan M., Finan, Chris, Schmidt, Amand F., Burgess, Stephen, Hingorani, Aroon D.
• Format: Article
• Language: English
• Subjects: Aged; Alzheimer Disease - genetics; Alzheimer's disease; Apolipoprotein B-100 - genetics; Cardiovascular disease; Cholesterol; Confidence intervals; Consortia; Coronary artery; Coronary artery disease; Exposure; Female; Genetic diversity; Genetic Predisposition to Disease - genetics; Genetics; Health risks; Heart diseases; Humans; Hydroxymethylglutaryl CoA Reductases - genetics; Identification methods; Inhibitors; Lipids; Low density lipoprotein; Male; Medicin och hälsovetenskap; Membrane Transport Proteins - genetics; Mendelian Randomization Analysis; Middle Aged; Models, Genetic; Neurodegenerative diseases; Pharmacovigilance; Polymorphism, Single Nucleotide - genetics; Proprotein Convertase 9 - genetics; Randomization; Regional analysis; Risk; Statins
• ISSN: 0364-5134; 1531-8249; 1531-8249
• DOI: 10.1002/ana.25642

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