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Cited by 96Dementia and Cognitive Impairment ResearchGenetic Associations and EpidemiologyAlzheimer's disease research and treatments

Repurposing antihypertensive drugs for the prevention of Alzheimer’s disease: A mendelian randomization study

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Walker, Venexia M, Kehoe, Patrick G, Martin, Richard M, Davies, Neil M·2020·International Journal of Epidemiology
DOI 10.1093/ije/dyz155PMC PMC7751008

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Abstract

Background: Evidence concerning the potential repurposing of antihypertensives for Alzheimer’s disease prevention is inconclusive. We used Mendelian randomization, which can be more robust to confounding by indication and patient characteristics, to investigate the effects of lowering systolic blood pressure, via the protein targets of different antihypertensive drug classes, on Alzheimer’s disease. Methods: We used summary statistics from genome-wide association studies of systolic blood pressure and Alzheimer’s disease in a two-sample Mendelian randomization analysis. We identified single-nucleotide polymorphisms (SNPs) that mimic the action of antihypertensive protein targets and estimated the effect of lowering systolic blood pressure on Alzheimer’s disease in three ways: (i) combining the protein targets of antihypertensive drug classes, (ii) combining all protein targets and (iii) without consideration of the protein targets. Results: There was limited evidence that lowering systolic blood pressure, via the protein targets of antihypertensive drug classes, affected Alzheimer’s disease risk. For example, the protein targets of calcium channel blockers had an odds ratio (OR) per 10 mmHg lower systolic blood pressure of 1.53 [95% confidence interval (CI): 0.94 to 2.49; p = 0.09; SNPs = 17]. We also found limited evidence for an effect when combining all protein targets (OR per 10 mmHg lower systolic blood pressure: 1.14; 95% CI: 0.83 to 1.56; p = 0.41; SNPs = 59) and without consideration of the protein targets (OR per 10 mmHg lower systolic blood pressure: 1.04; 95% CI: 0.95 to 1.13; p = 0.45; SNPs = 153). Conclusions: Mendelian randomization suggests that lowering systolic blood pressure via the protein targets of antihypertensive drugs is unlikely to affect the risk of developing Alzheimer’s disease. Consequently, if specific antihypertensive drug classes do affect the risk of Alzheimer’s disease, they may not do so via systolic blood pressure.

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  • 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 Walker et al., 2020

    The Results (‘Antihypertensive drug effect’) report little evidence for an overall effect on Alzheimer’s disease risk when the protein targets of antihypertensives were combined. But the ‘Drug class effects’ results identify exceptions, and the study’s limited evidence of an effect does not establish that antihypertensive drugs have little to no effect on risk. (LLM, conf=0.82)

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Authors
Walker, V. M., Kehoe, P. G., Martin, R. M., & Davies, N. M.
Affiliations
University of Bristol (GB)
Corresponding author
Walker, Venexia M
ORCID
Venue
International Journal of Epidemiology
Publisher
Oxford University Press (OUP)
Published
2019-07-23
Volume
49
Issue
4
Pages
1132-1140
ISSN
  • 0300-5771 (ISSN-L)
  • 1464-3685
DOI
10.1093/ije/dyz155
PMC
PMC7751008
OpenAlex
W2951397190
Cited by
96
References
6
Citations by year
2026: 7 · 2025: 14 · 2024: 23 · 2023: 14 · 2022: 11 · 2021: 18 · 2020: 7 · 2019: 2
FWCI
7.45
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Epidemiology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Bristol Research (University of Bristol) (publishedVersion, cc-by)
  • Explore Bristol Research (submittedVersion, cc-by)
Funders
  • Perros Trust
  • Integrative Epidemiology Unit
  • The Integrative Epidemiology Unit
  • Medical Research Council
  • University of Bristol (MC_UU_00011/1, MC_UU_00011/3)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
Alzheimer's disease, antihypertensive drugs, drug repurposing, systolic blood pressure, blood pressure reduction, calcium channel blockers, protein targets, Alzheimer's disease prevention, Mendelian randomization
MeSH terms
Alzheimer Disease, Antihypertensive Agents, Blood Pressure, Humans, Hypertension, Genome-Wide Association Study, Mendelian Randomization Analysis, Drug Repositioning

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