TY - JOUR
T1 - Lipid lowering and Alzheimer disease risk
T2 - A mendelian randomization study
AU - Williams, Dylan M.
AU - Finan, Chris
AU - Schmidt, Amand F.
AU - Burgess, Stephen
AU - Hingorani, Aroon D.
N1 - Funding Information:
D.M.W. received support for this work from the Foundation for Geriatric Diseases at Karolinska Institute (2018‐01252). A.F.S. is supported by BHF grant PG/18/5033837. We thank IGAP for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in the analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. We also thank the participants, researchers, and staff associated with the many other studies from which we used data for this report; and Drs I. Jansen, J. Savage, and D. Posthuma of the PGC for sharing additional data on the PGC GWAS sample to use in these analyses.
Funding Information:
D.M.W. received support for this work from the Foundation for Geriatric Diseases at Karolinska Institute (2018-01252). A.F.S. is supported by BHF grant PG/18/5033837. We thank IGAP for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in the analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. We also thank the participants, researchers, and staff associated with the many other studies from which we used data for this report; and Drs I. Jansen, J. Savage, and D. Posthuma of the PGC for sharing additional data on the PGC GWAS sample to use in these analyses.
Publisher Copyright:
© 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85076446790&partnerID=8YFLogxK
U2 - 10.1002/ana.25642
DO - 10.1002/ana.25642
M3 - Article
C2 - 31714636
AN - SCOPUS:85076446790
SN - 0364-5134
VL - 87
SP - 30
EP - 39
JO - Annals of Neurology
JF - Annals of Neurology
IS - 1
ER -