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Lipid lowering and Alzheimer's disease risk: a Mendelian randomization study

Williams, DM; Finan, C; Schmidt, AF; Burgess, S; Hingorani, AD; (2020) Lipid lowering and Alzheimer's disease risk: a Mendelian randomization study. Annals of Neurology , 87 (1) pp. 30-39. 10.1002/ana.25642. Green open access

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Abstract

Objective: To examine whether genetic variation affecting the expression or function of lipid-lowering drug targets isassociated with Alzheimer disease (AD) risk, to evaluate the potential impact of long-term exposure to correspondingtherapeutics.Methods: We conducted Mendelian randomization analyses using variants in genes that encode the protein targets ofseveral approved lipid-lowering drug classes: HMGCR (encoding the target for statins), PCSK9 (encoding the target forPCSK9 inhibitors, eg, evolocumab and alirocumab), NPC1L1 (encoding the target for ezetimibe), and APOB (encodingthe 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 forregional 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 classeswould affect AD risk. In contrast, genetically instrumented exposure to PCSK9 inhibitors was predicted to increase ADrisk in both of the AD samples (combined odds ratio per standard deviation lower LDL-C inducible by the drug tar-get = 1.45, 95% confidence interval = 1.23–1.69). This risk increase was opposite to, although more modest than, thedegree 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 ADprevention. Notwithstanding caveats to this genetic evidence, pharmacovigilance for AD risk among users of PCSK9inhibitors may be warranted.

Type: Article
Title: Lipid lowering and Alzheimer's disease risk: a Mendelian randomization study
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/ana.25642
Publisher version: https://doi.org/10.1002/ana.25642
Language: English
Additional information: Copyright © 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine > MRC Unit for Lifelong Hlth and Ageing
URI: https://discovery.ucl.ac.uk/id/eprint/10086065
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