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Low LDL cholesterol,PCSK9 and HMGCR genetic variation, and risk of Alzheimer’s disease and Parkinson’s disease: Mendelian randomisation study
Open accessAbstract
Objective To test the hypothesis that low density lipoprotein (LDL) cholesterol due to genetic variation in the genes responsible for LDL cholesterol metabolism and biosynthesis(PCSK9 and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), respectively) is associated with a high risk of Alzheimer’s disease, vascular dementia, any dementia, and Parkinson’s disease in the general population. Design Mendelian randomisation study. Setting Copenhagen General Population Study and Copenhagen City Heart Study. Participants 111 194 individuals from the Danish general population. Main outcome measures Risk of Alzheimer’s disease, vascular dementia, all dementia, and Parkinson’s disease. Results In observational analyses, the multifactorially adjusted hazard ratio for Parkinson’s disease in participants with an LDL cholesterol level <1.8 mmol/L versus ≥4.0 mmol/L was 1.70 (95% confidence interval 1.03 to 2.79), whereas the corresponding hazard ratios for Alzheimer’s disease, vascular dementia, or any dementia did not differ from 1.0. PCSK9 and HMGCR variants combined were associated with a 9.3% lower LDL cholesterol level. In genetic, causal analyses adjusted for age, sex, and year of birth, the risk ratios for a lifelong 1 mmol/L lower LDL cholesterol level were 0.57 (0.27 to 1.17) for Alzheimer’s disease, 0.81 (0.34 to 1.89) for vascular dementia, 0.66 (0.34 to 1.26) for any dementia, and 1.02 (0.26 to 4.00) for Parkinson’s disease. Summary level data from the International Genomics of Alzheimer’s Project using Egger Mendelian randomisation analysis gave a risk ratio for Alzheimer’s disease of 0.24 (0.02 to 2.79) for 26 PCSK9 and HMGCR variants, and of 0.64 (0.52 to 0.79) for 380 variants of LDL cholesterol level lowering. Conclusion Low LDL cholesterol levels due to PCSK9 and HMGCR variants had no causal effect on high risk of Alzheimer’s disease, vascular dementia, any dementia, or Parkinson’s disease; however, low LDL cholesterol levels may have a causal effect in reducing the risk of Alzheimer’s disease.
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“PCSK9 loss of function mutations carriers are at neutral risk of developing AD (86, 100, 101)”
From PCSK9 and the nervous system: a no-brainer? (2023) · cites this paper as [100]
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“there is no consensus for an association between PCSK9 genetic variants and AD”
From PCSK9 and the nervous system: a no-brainer? (2023) · cites this paper as [100]
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“Some genetic studies suggest that PCSK9 loss-of-function variants confer protection against AD, whereas others show no association.”
From The Roles of PCSK9 in Alzheimer’s Disease: A Systematic Review of Clinical, Genetic, and Preclinical Evidence (2025) · cites this paper as [23]
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“Similarly, Mendelian randomization studies—which test whether genetically determined changes in PCSK9 influence disease susceptibility—have generally suggested that PCSK9 is unlikely to be a causal determinant of AD [23].”
From The Roles of PCSK9 in Alzheimer’s Disease: A Systematic Review of Clinical, Genetic, and Preclinical Evidence (2025) · cites this paper as [23]
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“an analysis based on the Mendelian randomization approach in the Danish population enrolled in two different prospective studies evidenced no causal effects of PCSK9 genetic variants on the risk of AD and also of other forms of dementia and Parkinson’s disease [123].”
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 [123]
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“By contrast, genetic analyses—including GWAS and Mendelian randomization—generally failed to identify a causal link between PCSK9 and disease risk [23,25,26].”
From The Roles of PCSK9 in Alzheimer’s Disease: A Systematic Review of Clinical, Genetic, and Preclinical Evidence (2025) · cites this paper as [23]
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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 [9]
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“Similarly, preclinical work alternately supports pro-amyloidogenic effects, negligible impact, or even context-dependent neuroprotection.”
From The Roles of PCSK9 in Alzheimer’s Disease: A Systematic Review of Clinical, Genetic, and Preclinical Evidence (2025) · cites this paper as [23]
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“Examples of exposure sets where multivariable Mendelian randomization has been used include lipid fractions (such as high-density lipoprotein cholesterol, LDL-cholesterol, and triglycerides) 82 , and body composition measures (such as fat mass and fat-free mass) 83 .”
From Guidelines for performing Mendelian randomization investigations (2020) · cites this paper as [83]
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Metadata
- Authors
- Benn, M., Nordestgaard, B. G., Frikke-Schmidt, R., & Tybjærg-Hansen, A.
- Affiliations
- University of Copenhagen (DK)
- Corresponding author
- Benn, Marianne
- Venue
- BMJ
- Publisher
- BMJ
- Published
- 2017-04-24
- Volume
- 357
- Pages
- j1648
- ISSN
- 1756-1833 (ISSN-L)
- 0959-8138
- PMC
- PMC5421439
- OpenAlex
- W2607529696
- Cited by
- 178
- References
- 49
- Citations by year
- 2026: 11 · 2025: 14 · 2024: 22 · 2023: 14 · 2022: 21 · 2021: 23 · 2020: 22 · 2019: 18 · 2018: 22 · 2017: 10
- FWCI
- 20.18
- Type
- journal article
- Language
- en
- Update notices
- correction (2017-06-29)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- BMJ (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Sundhed og Sygdom, Det Frie Forskningsråd
- Gentofte Hospital
- Herlev Hospital
- Lundbeckfonden (R126-2012-12556, R211-2015-3977)
- Danmarks Frie Forskningsfond
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- low LDL cholesterol, PCSK9, HMGCR, Alzheimer's disease, Parkinson's disease, vascular dementia, dementia, LDL cholesterol metabolism, genetic variants
- MeSH terms
- Proprotein Convertase 9, Adult, Aged, Alzheimer Disease, Denmark, Female, Follow-Up Studies, Genotype, Humans, Hydroxymethylglutaryl CoA Reductases, Cholesterol, LDL, Male, Middle Aged, Parkinson Disease, Prospective Studies, Genetic Variation, Biomarkers, Proportional Hazards Models, Genetic Predisposition to Disease, Mendelian Randomization Analysis
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