Varenicline as a Repurposable Drug Candidate for ADRD Prevention
- 1Washington DC VA Medical Center, Washington, DC, United States; George Washington University, Washington, DC, United States
Abstract
ObjectiveEffective strategies to prevent Alzheimers disease and related dementias (ADRD) are limited. Implementing our Medication-Wide Association Study (MWAS+), we highlighted varenicline as a candidate. This study evaluated the association between varenicline use and risk of ADRD relative to nicotine replacement therapy (NRT).
MethodsUsing the All of Us Research Database, we identified adults aged 50 years or older with available lifestyle survey responses regarding tobacco use history who initiated smoking cessation therapy with either varenicline or NRT between 2006 and 2023. We limited our cohort to incident monotherapy users and designated the index date as the first prescription. Individuals with baseline ADRD or no follow-up were excluded. Baseline characteristics included demographics, comorbidities, BMI, and prior medication exposures. Outcomes were incident ADRD and a composite outcome of ADRD or death.
FindingsThe cohort consisted of 9,584 individuals (1,801 varenicline users and 7,783 NRT users). After propensity score matching, there were 1,758 individuals in each group with balanced baseline characteristics. Varenicline use was associated with a reduced risk of ADRD (HR 0.516, 95% CI: 0.353-0.754) and the composite outcome ADRD or death (HR 0.657, 95% CI: 0.501-0.861). Kaplan-Meier curves also demonstrated vareniclines sustained benefits through the study period.
ImplicationsVarenicline use is associated with a lower risk of ADRD among older adults receiving smoking cessation therapy. Further investigation of varenicline as a potential strategy for ADRD prevention is warranted. These findings underscored the value of explainable AI-guided approaches to drug repurposing.
HighlightO_LIArtificial Intelligence (AI) Medication-Wide Association Study (MWAS+) identified varenicline as candidate for ADRD prevention. C_LIO_LIVarenicline linked to lower ADRD risk vs NRT in propensity score matched cohort. C_LIO_LIConsistent results for ADRD and composite outcome ADRD or death. C_LI
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BibTeX
@misc{ma2026varenicline,
title = {{Varenicline as a Repurposable Drug Candidate for ADRD Prevention}},
author = {P. Ma and J. Zhou and Y. Cheng and J. E. McGeary and T. H. Taveira and A. Ahmed and W.-C. Wu and E. Zamrini and B. N. Dugger and L. N. C. Sevilla and J. A. Nations and Y. Shao and Y. Yin and D. W. Tsuang and M. W. Logue and S. Ayandeh and C. Faselis and S. J. Nelson and Q. Zeng-Treitler},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.17.26363232},
url = {https://www.medrxiv.org/content/10.64898/2026.09.17.26363232v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Varenicline as a Repurposable Drug Candidate for ADRD Prevention
AU - P. Ma
AU - J. Zhou
AU - Y. Cheng
AU - J. E. McGeary
AU - T. H. Taveira
AU - A. Ahmed
AU - W.-C. Wu
AU - E. Zamrini
AU - B. N. Dugger
AU - L. N. C. Sevilla
AU - J. A. Nations
AU - Y. Shao
AU - Y. Yin
AU - D. W. Tsuang
AU - M. W. Logue
AU - S. Ayandeh
AU - C. Faselis
AU - S. J. Nelson
AU - Q. Zeng-Treitler
PY - 2026
DA - 2026/09/17
PB - medRxiv
DO - 10.64898/2026.09.17.26363232
UR - https://www.medrxiv.org/content/10.64898/2026.09.17.26363232v1
AB - ObjectiveEffective strategies to prevent Alzheimers disease and related dementias (ADRD) are limited. Implementing our Medication-Wide Association Study (MWAS+), we highlighted varenicline as a candidate. This study evaluated the association between varenicline use and risk of ADRD relative to nicotine replacement therapy (NRT). MethodsUsing the All of Us Research Database, we identified adults aged 50 years or older with available lifestyle survey responses regarding tobacco use history who initiated smoking cessation therapy with either varenicline or NRT between 2006 and 2023. We limited our cohort to incident monotherapy users and designated the index date as the first prescription. Individuals with baseline ADRD or no follow-up were excluded. Baseline characteristics included demographics, comorbidities, BMI, and prior medication exposures. Outcomes were incident ADRD and a composite outcome of ADRD or death. FindingsThe cohort consisted of 9,584 individuals (1,801 varenicline users and 7,783 NRT users). After propensity score matching, there were 1,758 individuals in each group with balanced baseline characteristics. Varenicline use was associated with a reduced risk of ADRD (HR 0.516, 95% CI: 0.353-0.754) and the composite outcome ADRD or death (HR 0.657, 95% CI: 0.501-0.861). Kaplan-Meier curves also demonstrated vareniclines sustained benefits through the study period. ImplicationsVarenicline use is associated with a lower risk of ADRD among older adults receiving smoking cessation therapy. Further investigation of varenicline as a potential strategy for ADRD prevention is warranted. These findings underscored the value of explainable AI-guided approaches to drug repurposing. HighlightO_LIArtificial Intelligence (AI) Medication-Wide Association Study (MWAS+) identified varenicline as candidate for ADRD prevention. C_LIO_LIVarenicline linked to lower ADRD risk vs NRT in propensity score matched cohort. C_LIO_LIConsistent results for ADRD and composite outcome ADRD or death. C_LI
ER -