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Sex differences in genetic liability to modifiable Alzheimer’s disease risk factors
Sharma RU, Tolosa-Tort P, Okorie M, Chatterjee A, Jonson C, Yaffe K, Belloy ME, Andrews SJ et al.. medRxiv, 2026-10-06
Topic: Genetics and APOE
RESULTS Educational attainment and physical activity PRSs were associated with AD in both sexes. PRS sex differences were nominal for educational attainment, total cholesterol, and LDL cholesterol, but none remained significant after FDR correction. Genetic correlation showed FDR-significant sex differences for social isolation, physical activity, LDL cholesterol, and pulse pressure. MR identified FDR-significant associations within sex strata; higher HDL cholesterol was associated with lower AD risk in females, whereas higher total cholesterol and type 2 diabetes were associated with lower and higher AD risk, respectively, in males. Sensitivity analyses provided inconsistent support, and no sex difference in MR estimates remained significant after FDR correction. In HABS-HD, type 2 diabetes PRS was associated with higher NfL, BMI PRS with higher pTau 181 , and the composite PRS with higher NfL among males after FDR correction. Interpretatio The strongest evidence of sex heterogeneity for modifiable risk factors and AD was observed in their shared genetic architectures, with FDR-significant female–male differences for social isolation, physical activity, LDL cholesterol, and pulse pressure. PRS and Mendelian randomization analyses provided less evidence of formal sex heterogeneity, suggesting that sex differences in shared genetic architecture do not necessarily imply sex-specific causal effects.
Key findings
- RESULTS Educational attainment and physical activity PRSs were associated with AD in both sexes.
- PRS sex differences were nominal for educational attainment, total cholesterol, and LDL cholesterol, but none remained significant after FDR correction.
- Genetic correlation showed FDR-significant sex differences for social isolation, physical activity, LDL cholesterol, and pulse pressure.
- MR identified FDR-significant associations within sex strata; higher HDL cholesterol was associated with lower AD risk in females, whereas higher total cholesterol and type 2 diabetes were associated with lower and higher AD risk, respectively, in males.
- Sensitivity analyses provided inconsistent support, and no sex difference in MR estimates remained significant after FDR correction.
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Study details
- Study designsystematic review
- Participants27,751
- Evidence strengthHigh
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 58 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for effect reported 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 multi-centre collaboration, so those were left out: it earned 36 of the 62 points we could judge it on, which is 58 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 | 12 / 12 | A systematic review of all the studies on the question |
| Strength of evidence | 5 / 5 | Rated “high” 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 | 4 / 4 | 27,751 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | A review of other studies — randomisation is not credited here |
| 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 |
| Multi-centre 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 | 36 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 36 of the 62 points we could judge it on is 58 out of 100. |
| Total | 58 / 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 →
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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
Sharma, R. U., Tolosa-Tort, P., Okorie, M., Chatterjee, A., Jonson, C., Yaffe, K., et al. (2026). Sex differences in genetic liability to modifiable Alzheimer’s disease risk factors. medRxiv. https://doi.org/10.64898/2026.10.01.26364536
Vancouver
Sharma RU, Tolosa-Tort P, Okorie M, Chatterjee A, Jonson C, Yaffe K, et al. Sex differences in genetic liability to modifiable Alzheimer’s disease risk factors. medRxiv. 2026. doi:10.64898/2026.10.01.26364536.
BibTeX
@article{sharma2026-c65529a9,
author = {Sharma, R. U. and Tolosa-Tort, P. and Okorie, M. and Chatterjee, A. and Jonson, C. and Yaffe, K. and Belloy, M. E. and Andrews, S. J. and others},
title = {{Sex differences in genetic liability to modifiable Alzheimer’s disease risk factors}},
journal = {medRxiv},
year = {2026},
doi = {10.64898/2026.10.01.26364536},
url = {https://doi.org/10.64898/2026.10.01.26364536}
}
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