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Mendelian Randomization Study of PCSK9 and HMG-CoA Reductase Inhibition and Cognitive Function
Open accessAbstract
BACKGROUND: Lipid-lowering therapy with statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition are effective strategies in reducing cardiovascular disease risk; however, concerns remain about potential long-term adverse neurocognitive effects. OBJECTIVES: This genetics-based study aimed to evaluate the relationships of long-term PCSK9 inhibition and statin use on neurocognitive outcomes. METHODS: We extracted single-nucleotide polymorphisms in 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and PCSK9 from predominantly European ancestry-based genome-wide association studies summary-level statistics of low-density lipoprotein cholesterol and performed drug-target Mendelian randomization, proxying the potential neurocognitive impact of drug-based PCSK9 and HMGCR inhibition using a range of outcomes to capture the complex facets of cognition and dementia. RESULTS: Using data from a combined sample of ∼740,000 participants, we observed a neutral cognitive profile related to genetic PCSK9 inhibition, with no significant effects on cognitive performance, memory performance, or cortical surface area. Conversely, we observed several adverse associations for HMGCR inhibition with lowered cognitive performance (beta: -0.082; 95% CI: -0.16 to -0.0080; P = 0.03), reaction time (beta = 0.00064; 95% CI: 0.00030-0.00098; P = 0.0002), and cortical surface area (beta = -0.18; 95% CI: -0.35 to -0.014; P = 0.03). Neither PCSK9 nor HMGCR inhibition impacted biomarkers of Alzheimer's disease progression or Lewy body dementia risk. Consistency of findings across Mendelian randomization methods accommodating different assumptions about genetic pleiotropy strengthens causal inference. CONCLUSIONS: Using a wide range of cognitive function and dementia endpoints, we failed to find genetic evidence of an adverse PCSK9-related impact, suggesting a neutral cognitive profile. In contrast, we observed adverse neurocognitive effects related to HMGCR inhibition, which may well be outweighed by the cardiovascular benefits of statin use, but nonetheless may warrant pharmacovigilance.
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“in some trials, PCSK9 inhibitors including evolocumab do not show the effects on cognitive decline and complain in a large clinical trial [33, 34].”
From Blood PCSK9 Impacts Alzheimer's Disease Risk in an APOE Genotype‐Dependent Manner: A Prospective Cohort Study (2026) · cites this paper as [34]
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“However, the relationship between PCSK9 and AD is still largely unknown, as genetic studies have given opposite indications of the association between PCSK9 variants and AD predisposition [8,9,10].”
From PCSK9 affects astrocyte cholesterol metabolism and reduces neuron cholesterol supplying in vitro: potential implications in Alzheimer’s disease (2022) · cites this paper as [10]
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Metadata
- Authors
- Rosoff, D. B., Bell, A. S., Jung, J., Wagner, J., Mavromatis, L. A., & Lohoff, F. W.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Lohoff, Falk W.
- ORCID
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2022-08
- Volume
- 80
- Issue
- 7
- Pages
- 653-662
- ISSN
- 0735-1097 (ISSN-L)
- OpenAlex
- W4290721542
- Cited by
- 126
- References
- 64
- Citations by year
- 2026: 16 · 2025: 44 · 2024: 41 · 2023: 22 · 2022: 3
- FWCI
- 26.52
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- University of Bristol
- National Institutes of Health (ZIA-AA000242)
- Medical Research Council
- National Institute on Alcohol Abuse and Alcoholism
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
- Keywords
- PCSK9 inhibition, HMG-CoA reductase inhibition, statins, cognitive function, dementia risk, Alzheimer's disease biomarkers, dementia with Lewy bodies, cortical surface area, reaction time, memory performance, LDL cholesterol, pleiotropy, pharmacovigilance
- MeSH terms
- Proprotein Convertase 9, Acyl Coenzyme A, Alzheimer Disease, Cognition, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Genome-Wide Association Study, Mendelian Randomization Analysis
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