The DOI matches its Crossref record; 61 of the 64 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“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]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“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]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Sudlow, C., Gallacher, J., Allen, N., Beral, V., Burton, P., Danesh, J., Downey, P., Elliott, P., Green, J., Landray, M., et al. (2015) · PLOS Medicine · doi:10.1371/journal.pmed.1001779 · Cited by 12,728
The MR-Base platform supports systematic causal inference across the human phenome
Hemani, G., Zheng, J., Elsworth, B., Wade, K. H., Haberland, V., Baird, D., Laurin, C., Burgess, S., Bowden, J., Langdon, R., et al. (2018) · eLife · doi:10.7554/elife.34408 · Cited by 7,959
Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease
Sabatine, M. S., Giugliano, R. P., Keech, A. C., Honarpour, N., Wiviott, S. D., Murphy, S. A., Kuder, J. F., Wang, H., Liu, T., Wasserman, S. M., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1615664 · Cited by 6,138
Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians
Davies, N. M., Holmes, M. V., & Davey Smith, G. (2018) · BMJ · doi:10.1136/bmj.k601 · Cited by 4,404
Fry, A., Littlejohns, T. J., Sudlow, C., Doherty, N., Adamska, L., Sprosen, T., Collins, R., & Allen, N. E. (2017) · American Journal of Epidemiology · doi:10.1093/aje/kwx246 · Cited by 3,979
Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome
Schwartz, G. G., Steg, P. G., Szarek, M., Bhatt, D. L., Bittner, V. A., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1801174 · Cited by 3,634
Scientists rise up against statistical significance
Amrhein, V., Greenland, S., & McShane, B. (2019) · Nature · doi:10.1038/d41586-019-00857-9 · Cited by 2,983
Willer (2013) · doi:10.1038/ng.2797 · Cited by 2,983
Alzheimer's Disease Neuroimaging Initiative (ADNI)
Petersen, R. C., Aisen, P. S., Beckett, L. A., Donohue, M. C., Gamst, A. C., Harvey, D. J., Jack, C. R., Jagust, W. J., Shaw, L. M., Toga, A. W., et al. (2010) · Neurology · doi:10.1212/wnl.0b013e3181cb3e25 · Cited by 2,572
23andMe Research Team, Lee, J. J., COGENT (Cognitive Genomics Consortium), Social Science Genetic Association Consortium, Wedow, R., Okbay, A., Kong, E., Maghzian, O., Zacher, M., Nguyen-Viet, T. A., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0147-3 · Cited by 2,470
Research works printed but not linked: 3
- Nikpay, 2015, A comprehensive 1,000 genomes-based genome-wide association meta-analysis of coronary artery disease, Nat Genet, 47, 1121
- Hemani, 2018, The MR-Base platform supports systematic causal inference across the human phenome, Elife, 7, 10.7554/eLife.34408 · DOI · Paper page
- Schultz, 2018, The role of statins in both cognitive impairment and protection against dementia: a tale of two mechanisms, Transl Neurodegener, 7, 10.1186/s40035-018-0110-3 · DOI
Cited by
Sorted by citations
Items 101–127 of 127
Chen, J., Guo, X., & Song, H. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1346562
Xu, L., Wang, L., Wang, Y., Wang, Y., Jiang, Y., Du, P., Cheng, J., Zhang, C., Wang, R., Jiao, T., et al. (2024) · Research Square · doi:10.21203/rs.3.rs-4008037/v1
Lipid-lowering drug targets and lung related diseases: a Mendelian randomization study
Yu, H., Zhang, X., Wen, B., Hu, S., & Ni, B. (2024) · All Life · doi:10.1080/26895293.2024.2329440
Luo, S., Lam, H. S., Chan, Y. H., Tang, C. S.-M., He, B., Kwok, M. K., Leung, G. M., Schooling, C. M., & Yeung, S. L. A. (2023) · Figshare · doi:10.6084/m9.figshare.24465040
Wang, Q., Yang, Z., Zhao, P., Lin, X., Wen, S., Zhang, X., & Xu, Y. (2025) · SSRN Electronic Journal · doi:10.2139/ssrn.5080363
Lipid‐Lowering Drugs and Pulmonary Vascular Disease: A Mendelian Randomization Study
Yuan, X., Hong, P., & Zhou, J. (2025) · Pulmonary Circulation · doi:10.1002/pul2.70043
Insights into drug adverse reactions prediction through Mendelian randomization: a review
Huang, Z., Gong, H., Sun, X., Yi, W., Liang, S., Yang, S., Sun, Q., & Yan, X. (2025) · Postgraduate Medical Journal · doi:10.1093/postmj/qgae203
He, J., Wu, J., Tan, J., Yang, P., Bai, T., Song, J., Hou, X., & Zhang, L. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.114282
Li, M., Kooijman, S., van Dijk, K. W., Kastelein, J. J. P., Rensen, P. C. N., & Noordam, R. (2025) · medRxiv · doi:10.1101/2025.03.31.25324957
Giorgi, R. D., Waters, S., Gillespie, A. L., Quinton, A. M. G., Colwell, M., Murphy, S. E., Cowen, P. J., & Harmer, C. J. (2025) · Psychological Medicine · doi:10.1017/s0033291725001187
Aru, N., Yang, C., Chen, Y., & Liu, J. (2025) · Medicine · doi:10.1097/md.0000000000042685
Zhang, X., Yang, Z., & Huang, R. (2025) · Clinical Medicine and Pharmacology · doi:10.70731/91pd8g49
Zuo, Y., Chen, L., He, M., Du, J., & Tang, W. (2025) · Journal of clinical lipidology · doi:10.1016/j.jacl.2025.06.024
Do PCSK9 Inhibitors Impair Memory? A Dual Approach Combining Real-World Data and Genetic Evidence
Shi, X., Wang, S., Yang, Y., Xia, X., Fan, J., Wang, J., Wang, N., & Jia, X. (2025) · Pharmacy · doi:10.3390/pharmacy13050125
Wang, Y., Lü, L., Gong, S., Li, G., Luo, J., & Wu, D. (2025) · Research Square · doi:10.21203/rs.3.rs-6270740/v1
Liu, D., Liu, J., Mao, W., Li, X., Hu, B., Zhang, L., & Hu, J. Y. (2025) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0000000000001778
Xie, W., Li, J., Du, H., & Xia, J. (2023) · Figshare · doi:10.6084/m9.figshare.23949684
Luo, S., Lam, H. S., Chan, Y. H., Tang, C. S. M., He, B., Kwok, M. K., Leung, G. M., Schooling, C. M., & Au Yeung, S. L. (2024) · Figshare · doi:10.6084/m9.figshare.24465344
Mendelian randomization analysis of lipid-lowering drug targets and neuropsychiatric disorders
Peng, S., Liu, M., Du, F., & Li, K. (2025) · Medicine · doi:10.1097/md.0000000000046493
Huang, K., & Ren, J. P. (2026) · The Journal of Cardiovascular Aging · doi:10.20517/jca.2025.33
Xiao, H., Zeng, X., Pang, Q., Chen, H., & Lai, S. (2026) · Transplant Immunology · doi:10.1016/j.trim.2026.102385
Hariharan, P., Bagheri, M., & Sellke, F. (2026) · medRxiv · doi:10.64898/2026.06.02.26354765
SAIMSARA (2026) · SAIMSARA Journal · doi:10.62487/saimsarac25dcb0d
PCSK9 inhibitors do not increase cognitive risk
Ni, D., Feng, Z., Liang, D., Qi, Z., Lu, Y., Zhu, L., & Li, G. (2026) · Biology Direct · doi:10.1186/s13062-026-00865-6
Jaiswal, V., Deb, N., Latif, F., Shrestha, A. B., Garimella, V., Shama, N., Jitta, S. R., Naz, S., Kumar, T., Khan, S., et al. (2026) · The American Journal of Medicine · doi:10.1016/j.amjmed.2026.06.034
Cognitive safety of statin use in the elderly: Evidence from a nationally representative sample
Ding, J., Miao, J., Zhang, L., Liu, Q., Zhang, Y., Li, J., & Li, Y. (2026) · Journal of Internal Medicine · doi:10.1111/joim.70159
Gau, S.-Y., Lo, S., HSU, C., Tu, Y.-F., Su, Y.-J., Chen, C.-C., Wu, M.-C., Mitsukura, Y., & Chang, H.-C. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1942691
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
