Mendelian Randomization Study of PCSK9 and HMG-CoA Reductase Inhibition and Cognitive Function
Rosoff DB, Bell AS, Jung J, Wagner J, Mavromatis LA, Lohoff FW.. Journal of the American College of Cardiology, 2022-08-01
Topic: Brain proteins, microglia and lab models
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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APA 7th
Rosoff, D. B., Bell, A. S., Jung, J., Wagner, J., Mavromatis, L. A., & Lohoff, F. W. (2022). Mendelian Randomization Study of PCSK9 and HMG-CoA Reductase Inhibition and Cognitive Function. Journal of the American College of Cardiology. https://doi.org/10.1016/j.jacc.2022.05.041
Vancouver
Rosoff DB, Bell AS, Jung J, Wagner J, Mavromatis LA, Lohoff FW. Mendelian Randomization Study of PCSK9 and HMG-CoA Reductase Inhibition and Cognitive Function. Journal of the American College of Cardiology. 2022. doi:10.1016/j.jacc.2022.05.041. PMID: 35953131.
BibTeX
@article{rosoff2022-35953131,
author = {Rosoff, D. B. and Bell, A. S. and Jung, J. and Wagner, J. and Mavromatis, L. A. and Lohoff, F. W.},
title = {{Mendelian Randomization Study of PCSK9 and HMG-CoA Reductase Inhibition and Cognitive Function}},
journal = {Journal of the American College of Cardiology},
year = {2022},
doi = {10.1016/j.jacc.2022.05.041},
pmid = {35953131},
url = {https://doi.org/10.1016/j.jacc.2022.05.041}
}
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Key findings
- 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).
- 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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Study details
- Participants740,000
- Evidence strengthLow
How this study scored 52/100
Published in a peer-reviewed journal. Scored zero for study design, effect reported and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 30 of the 58 points we could judge it on, which is 52 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Journal of the American College of Cardiology) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2022 — within 6 year(s) of the newest study here |
| Sample size | 4 / 4 | 740,000 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 35953131) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 30 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 30 of the 58 points we could judge it on is 52 out of 100. |
| Total | 52 / 100 | — |
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