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The effects of nicotine on neurocognitive outcomes: evidence from a polygenic risk score analysis
Khatun T, Bothongo P, Williams DM, Khouja J, Anderson EL.. medRxiv, 2025-12-02
Topic: Air pollution and environmental exposures
Plain-language summary
Introduction The long-term nicotine effects on neurocognitive outcomes remain unclear. This knowledge gap is critical given rising nicotine product use in the UK, and the global dementia burden. Polygenic risk score (PRS) analyses allow us to explore the direct effects of nicotine on neurocognitive outcomes in a way that mitigates bias by confounding and reverse causation, which current research has not been able to achieve so far. We utilised PRSs for nicotine metabolite ratio (NMR) and cigarettes smoked per day (CPD) to investigate the direct effects of nicotine on a range of neurocognitive outcomes. Methods Using 334,757 participants from the UK Biobank cohort study, we tested whether an NMR PRS affects the risk of six major neurocognitive outcomes: all-cause dementia (ACD), Alzheimer’s disease (AD), all-cause Parkinson’s disease (ACP), vascular dementia (VAD), total white matter hyperintensity volume (WMHv), and fluid intelligence score (FI). Results Increased nicotine metabolism (indicating increased nicotine clearance from the body and therefore reduced nicotine exposure per cigarette smoked) was associated with decreased risk of AD in multivariable analyses with CPD adjusted for (OR = 0.95, 95% CI 0.91 to 1.00) (i.e. increased nicotine exposure increases AD risk). Additionally, smoking heaviness adversely affected WMHv in multivariable analyses adjusting for NMR (β = 0.04, 95% CI -0.005 to 0.09). Our findings for nicotine and smoking heaviness in relation to our other neurocognitive outcomes indicate small effect sizes and confidence intervals cross the null. Conclusion Our findings demonstrate differential effects of nicotine on AD risk and smoking intensity on white matter integrity, requiring triangulation with complementary methodological approaches to better inform potential long-term risks of nicotine intake on neurocognitive outcomes.
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APA 7th
Khatun, T., Bothongo, P., Williams, D. M., Khouja, J., & Anderson, E. L. (2025). The effects of nicotine on neurocognitive outcomes: evidence from a polygenic risk score analysis. medRxiv. https://doi.org/10.64898/2025.11.27.25341175
Vancouver
Khatun T, Bothongo P, Williams DM, Khouja J, Anderson EL. The effects of nicotine on neurocognitive outcomes: evidence from a polygenic risk score analysis. medRxiv. 2025. doi:10.64898/2025.11.27.25341175.
BibTeX
@article{khatun2025-c10227f5,
author = {Khatun, T. and Bothongo, P. and Williams, D. M. and Khouja, J. and Anderson, E. L.},
title = {{The effects of nicotine on neurocognitive outcomes: evidence from a polygenic risk score analysis}},
journal = {medRxiv},
year = {2025},
doi = {10.64898/2025.11.27.25341175},
url = {https://doi.org/10.64898/2025.11.27.25341175}
}
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Key findings
- Results Increased nicotine metabolism (indicating increased nicotine clearance from the body and therefore reduced nicotine exposure per cigarette smoked) was associated with decreased risk of AD in multivariable analyses with CPD adjusted for (OR = 0.95, 95% CI 0.91 to 1.00) (i.e. increased nicotine exposure increases AD risk).
- Our findings for nicotine and smoking heaviness in relation to our other neurocognitive outcomes indicate small effect sizes and confidence intervals cross the null.
- Conclusion Our findings demonstrate differential effects of nicotine on AD risk and smoking intensity on white matter integrity, requiring triangulation with complementary methodological approaches to better inform potential long-term risks of nicotine intake on neurocognitive outcomes.
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Study details
- Study designcohort study
- Participants334,757
- Effect sizeOR = 0.95
- Evidence strengthModerate
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 50 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for randomized / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multicenter collaboration, so those were left out: it earned 31 of the 62 points we could judge it on, which is 50 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (medRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 7 / 12 | A cohort study following people over time |
| 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 | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 4 / 4 | 334,757 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) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| 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 | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multicenter collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 31 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 31 of the 62 points we could judge it on is 50 out of 100. |
| Total | 50 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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