Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer's disease
- PMID: 35572351
- PMCID: PMC9097949
- DOI: 10.1038/s43587-021-00138-z
Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer's disease
Erratum in
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Author Correction: Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer's disease.Nat Aging. 2023 Jul;3(7):908. doi: 10.1038/s43587-023-00396-z. Nat Aging. 2023. PMID: 37118557 No abstract available.
Abstract
We developed an endophenotype disease module-based methodology for Alzheimer's disease (AD) drug repurposing and identified sildenafil as a potential disease risk modifier. Based on retrospective case-control pharmacoepidemiologic analyses of insurance claims data for 7.23 million individuals, we found that sildenafil usage was significantly associated with a 69% reduced risk of AD (hazard ratio = 0.31, 95% confidence interval 0.25-0.39, P<1.0×10-8). Propensity score stratified analyses confirmed that sildenafil is significantly associated with a decreased risk of AD across all four drug cohorts we tested (diltiazem, glimepiride, losartan and metformin) after adjusting age, sex, race, and disease comorbidities. We also found that sildenafil increases neurite growth and decreases phospho-tau expression in AD patient-induced pluripotent stem cells-derived neuron models, supporting mechanistically its potential beneficial effect in Alzheimer's disease. The association between sildenafil use and decreased incidence of AD does not establish causality or its direction, which requires a randomized clinical trial approach.
Conflict of interest statement
Competing interests. Dr. Cummings has provided consultation to Acadia, Actinogen, Alkahest, Alzheon, Annovis, Avanir, Axsome, Biogen, BioXcel, Cassava, Cerecin, Cerevel, Cortexyme, Cytox, EIP Pharma, Eisai, Foresight, GemVax, Genentech, Green Valley, Grifols, Karuna, Merck, Novo Nordisk, Otsuka, Resverlogix, Roche, Samumed, Samus, Signant Health, Suven, Third Rock, and United Neuroscience pharmaceutical and assessment companies. Dr. Cummings has stock options in ADAMAS, AnnovisBio, MedAvante, and BiOasis. The other authors have declared no competing interest.
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Comment in
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A needle for Alzheimer's in a haystack of claims data.Nat Aging. 2021 Dec;1(12):1083-1085. doi: 10.1038/s43587-021-00139-y. Nat Aging. 2021. PMID: 37117523 No abstract available.
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Reply to: Comparator choices in pharmacoepidemiology studies of Alzheimer's disease.Nat Aging. 2023 Jul;3(7):793-795. doi: 10.1038/s43587-023-00418-w. Epub 2023 May 22. Nat Aging. 2023. PMID: 37217662 No abstract available.
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Comparator choices in pharmacoepidemiology studies of Alzheimer's disease.Nat Aging. 2023 Jul;3(7):791-792. doi: 10.1038/s43587-023-00417-x. Epub 2023 May 22. Nat Aging. 2023. PMID: 37217663 No abstract available.
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