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Varenicline as a Repurposable Drug Candidate for ADRD Prevention
Ma, P.; Zhou, J.; Cheng, Y.; McGeary, J. E.; Taveira, T. H.; Ahmed, A.; Wu, W.-C.; Zamrini et al.. medRxiv (preprint), 2026-09-20
Topic: Brain proteins, microglia and lab models
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
Key findings
- 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.
- These findings underscored the value of explainable AI-guided approaches to drug repurposing.
- C_LIO_LIConsistent results for ADRD and composite outcome ADRD or death.
Why it matters
In a database study, older adults who took varenicline for smoking cessation had a lower risk of developing Alzheimer's disease and related dementias than those who used nicotine replacement therapy. This is observational evidence only, and the authors call for further research before varenicline could be considered for prevention.
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Study details
- Participants9,584
- Effect sizeHR 0.516; HR 0.657
- Evidence strengthModerate
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 36 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design and randomised / blinded because the record does not state it. We have no data on impact for its field and year, so that was left out: it earned 34 of the 94 points we could judge it on, which is 36 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (medRxiv (preprint)) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 3 / 4 | 9,584 participants |
| Effect reported | 3 / 3 | Effect reported with a statistic (interval, p-value, ratio or similar) |
| 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 | 0 / 7 | Cited 0 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.0 citations a year over 2 year(s) since 2026 |
| 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 | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 0 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Qing Zeng‐Treitler: h-index 29 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | University of Washington: institution h-index 3,540 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 13 institution(s) in 1 country |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 2 / 2 | Free to read |
| Points | 34 / 94 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 34 of the 94 points we could judge it on is 36 out of 100. |
| Total | 36 / 100 | Capped to 16 because this is not a peer-reviewed article. |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Ma, P., Zhou, J., Cheng, Y., McGeary, J. E., Taveira, T. H., Ahmed, A., et al. (2026). Varenicline as a Repurposable Drug Candidate for ADRD Prevention. medRxiv (preprint). https://doi.org/10.64898/2026.09.17.26363232
Vancouver
Ma P, Zhou J, Cheng Y, McGeary JE, Taveira TH, Ahmed A, et al. Varenicline as a Repurposable Drug Candidate for ADRD Prevention. medRxiv (preprint). 2026. doi:10.64898/2026.09.17.26363232.
BibTeX
@article{ma2026-a6a56bb0,
author = {Ma, P. and Zhou, J. and Cheng, Y. and McGeary, J. E. and Taveira, T. H. and Ahmed, A. and Wu, W.-C. and Zamrini and others},
title = {{Varenicline as a Repurposable Drug Candidate for ADRD Prevention}},
journal = {medRxiv (preprint)},
year = {2026},
doi = {10.64898/2026.09.17.26363232},
url = {https://doi.org/10.64898/2026.09.17.26363232}
}
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