Lipid lowering and Alzheimer disease risk: A mendelian randomization study
Open accessAbstract
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
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Only one of the reviewed studies reported evidence of increased AD risk associated with drug use, specifically for the PCSK9 inhibitors evolocumab and alirocumab.
“Only one of the reviewed studies reported evidence of increased AD risk associated with drug use, specifically for the PCSK9 inhibitors evolocumab and alirocumab (Williams et al., 2020).”
From Drug repurposing for Alzheimer’s disease from 2012–2022—a 10-year literature review (2023) · cites this paper as Williams et al., 2020
The Results report a genetically predicted increase in Alzheimer disease risk for inhibition of PCSK9, and the Methods identify evolocumab and alirocumab as examples of PCSK9 inhibitors (pages not provided). But the Discussion cautions that this genetic prediction may not apply to use of those drugs in practice; the study did not establish increased risk among their users. The claim that this was the only reviewed study is the citing authors’ review framing, not a finding assessed here. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDrug target MR uses genetic variants in genes encoding drug targets to mimic the actions of drugs and estimate therapeutic potential.
“As an extension of MR, drug target MR has emerged as efficient way to estimate therapeutic potential by using genetic variants in genes encoding drug targets (referred to as cis variants) to mimic the actions of drugs.”
From Genetic insights into causal effects of lipids and lipid-modifying targets on calcific aortic valve stenosis: a Mendelian randomized study (2025) · cites this paper as [14]
Undesirable side effects of PCSK9-targeting therapy have been questioned in terms of cognitive function.
“Indeed, the occurrence of undesirable side effects has been questioned in terms of cognitive function [196,197] and negative impact on the immune system regulation that could lead to different inflammatory diseases [104].”
From The Emerging Role of PCSK9 in the Pathogenesis of Alzheimer’s Disease: A Possible Target for the Disease Treatment (2024) · cites this paper as [197]
The drugs with evidence of little to no effect on AD risk included lipid-lowering agents (ezetimibe, mipomersen, and statins), antihypertensives, dimethyl fumarate, and drugs commonly used in treatment of rheumatoid arthritis (tofacitinib, tocilizumab, and TNF inhibitors).
“These drugs included lipid-lowering agents (ezetimibe, mipomersen, and statins) (Williams et al., 2020), antihypertensives (Walker et al., 2020), dimethyl fumarate (approved for the treatment of multiple sclerosis) (Möhle et al., 2021), and drugs commonly used in treatment of rheumatoid arthritis (tofacitinib, tocilizumab, and TNF inhibitors) (Desai et al., 2022).”
From Drug repurposing for Alzheimer’s disease from 2012–2022—a 10-year literature review (2023) · cites this paper as Williams et al., 2020
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- Authors
- Williams, D. M., Finan, C., Schmidt, A. F., Burgess, S., & Hingorani, A. D.
- Affiliations
- University of London (GB)
- British Heart Foundation (GB)
- University Medical Center Utrecht (NL)
- University of Cambridge (GB)
- Corresponding author
- Williams, Dylan M.
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2019-12-13
- Volume
- 87
- Issue
- 1
- Pages
- 30-39
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC6944510
- OpenAlex
- W2987364071
- Cited by
- 157
- References
- 49
- Citations by year
- 2026: 7 · 2025: 18 · 2024: 51 · 2023: 40 · 2022: 9 · 2021: 27 · 2020: 4
- FWCI
- 2.06
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Annals of Neurology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- British Heart Foundation (PG/18/5033837)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- Alzheimer's disease risk, lipid-lowering drugs, PCSK9 inhibitors, statins, ezetimibe, mipomersen, HMGCR, NPC1L1, apolipoprotein B, LDL cholesterol, drug repurposing, pharmacovigilance, genetic variants
- MeSH terms
- Proprotein Convertase 9, Aged, Alzheimer Disease, Female, Humans, Hydroxymethylglutaryl CoA Reductases, Male, Middle Aged, Models, Genetic, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Membrane Transport Proteins, Apolipoprotein B-100, Mendelian Randomization Analysis
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