Potential Synergistic Association of Donepezil and Metformin With COVID-19 Mortality in Dementia Patients

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ID: 337654
2026
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Abstract
Abstract Background Older adults with dementia face markedly elevated mortality from COVID-19. Both donepezil and metformin have anti-inflammatory effects and are associated with improved outcomes in respiratory viral infections, but whether their combined use is associated with lower COVID-19 mortality remains unknown. Methods We conducted a retrospective cohort study using the National Clinical Cohort Collaborative (N3C) data enclave, including adults aged ≥65 years with primary SARS-CoV-2 infection. We evaluated the association between donepezil monotherapy (5 mg or 10 mg) and COVID-19 mortality using 1-to-1 propensity score-matched analyses. Analyses were stratified by diabetes and metformin use. Results Among patients with dementia, 30-day mortality was lower in patients receiving donepezil 5 mg compared with matched untreated controls (10.3% vs 13.2%; p = 0.00046) and similarly for 10 mg (10.3% vs 13.4%; p = 0.0014). Among patients with dementia and diabetes, donepezil–metformin use was associated with the lowest mortality, approaching levels in matched individuals without dementia or diabetes. Metformin or donepezil alone was associated with modest reductions. Among donepezil users, those with diabetes treated with metformin had lower mortality than those without diabetes (30-day: 7.6% vs 10.2%, p = 0.016; significant only after FDR correction). No significant mortality differences by diabetes or metformin use were observed among dementia patients not receiving donepezil. Conclusions Donepezil use was associated with reduced COVID-19 mortality in older adults with dementia, with findings consistent with a potential synergistic association with metformin. These findings warrant further study of cholinergic modulation, alone or with metabolic therapies, to reduce severe COVID-19 outcomes.
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Authors Bingnan Li, Andreas Handel, Ye Shen, Yuan Ke, Joy A. Phillips, Veronika I. Zarnitsyna, Adam B Wilcox, Adam M. Lee, Alexis Graves, Alfred (Jerrod) Anzalone, Amin Manna, Amit Saha, Amy L. Olex, Andrea Zhou, Andrew E Williams, Andrew M. Southerland, Andrew T. Girvin, Anita Walden, Anjali Alatkar Sharathkumar, Benjamin Amor, Benjamin A. Bates, Brian M. Hendricks, Brijesh D. Patel, G Caleb Alexander, Carolyn T. Bramante, Cavin K Ward-Caviness, Charisse Madlock‐Brown, Christine Suver, Christopher G. Chute, Christopher Dillon, Chunlei Wu, Clare Schmitt, Cliff M. Takemoto, Dan Housman, Davera L Gabriel, David A. Eichmann, Diego R Mazzotti, Donald E. Brown, Eilis Ann Boudreau, Elaine Hill, Emily Carlson Marti, Emily Pfaff, Evan French, Farrukh M. Koraishy, Federico Mariona, Fred Prior, George G. Sokos, Greg Martin, Harold P. Lehmann, Heidi M. Spratt, Hemalkumar B. Mehta, J.W. Awori Hayanga, Jami D. Pincavitch, Jaylyn Clark, Jeremy Richard Harper, Jessica Y. Islam, Jin Ge, Joel Joseph Gagnier, Johanna Jean Loomba, John B. Buse, Jomol Mathew, Joni L. Rutter, Julie A. McMurry, Justin Guinney, Justin B. Starren, Karen Crowley, Katie R. Bradwell, Kellie M Walters, Ken Wilkins, Kenneth R. Gersing, Kenrick Cato, Kimberly A. Murray, Kristin Kostka, Lavance Northington, Lee A. Pyles, Lesley Cottrell, Lili Portilla, Mariam Deacy, Mark M. Bissell, Marshall Clark, Mary S. Emmett, Matvey B. Palchuk, Melissa Anne Haendel, Meredith Adams, Meredith Temple-O'Connor, Michael G. Kurilla, Michele Morris, Nasia Safdar, Nicole Garbarini, Noha Sharafeldin, Ofer Sadan, Patricia A. Francis, Penny Wung Burgoon, Philip Payne, Randeep Singh Jawa, Rebecca A. Erwin-Cohen, Rena C. Patel, Richard A. Moffitt, Richard L. Zhu, Rishikesan Kamaleswaran
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Journal The Journal of infectious diseases
Year 2026
DOI
10.1093/infdis/jiag528
URL
https://doi.org/10.1093/infdis/jiag528
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