Leading mediators of sex differences in the incidence of dementia in community-dwelling adults in the UK Biobank: a retrospective cohort study
Open accessAbstract
Background: Little is known regarding whether sex assigned at birth modifies the association between several predictive factors for dementia and the risk of dementia itself. Methods: Our retrospective cohort study included 214,670 men and 214,670 women matched by age at baseline from the UK Biobank. Baseline data were collected between 2006 and 2010, and incident dementia was ascertained using hospital inpatient or death records until January 2021. Mediation analysis was tested for 133 individual factors. Results: Over 5,117,381 person-years of follow-up, 5928 cases of incident all-cause dementia (452 cases of young-onset dementia, 5476 cases of late-onset dementia) were documented. Hazard ratios (95% CI) for all-cause, young-onset, and late-onset dementias associated with the male sex (female as reference) were 1.23 (1.17–1.29), 1.42 (1.18–1.71), and 1.21 (1.15–1.28), respectively. Out of 133 individual factors, the strongest mediators for the association between sex and incident dementia were multimorbidity risk score (percentage explained (95% CI): 62.1% (45.2–76.6%)), apolipoprotein A in the blood (25.5% (15.2–39.4%)), creatinine in urine (24.9% (16.1–36.5%)), low-density lipoprotein cholesterol in the blood (23.2% (16.2–32.1%)), and blood lymphocyte percentage (21.1% (14.5–29.5%)). Health-related conditions (percentage (95% CI) explained: 74.4% (51.3–88.9%)) and biomarkers (83.0% (37.5–97.5%)), but not lifestyle factors combined (30.1% (20.7–41.6%)), fully mediated sex differences in incident dementia. Health-related conditions combined were a stronger mediator for late-onset (75.4% (48.6–90.8%)) than for young-onset dementia (52.3% (25.8–77.6%)), whilst lifestyle factors combined were a stronger mediator for young-onset (42.3% (19.4–69.0%)) than for late-onset dementia (26.7% (17.1–39.2%)). Conclusions: Our analysis matched by age has demonstrated that men had a higher risk of all-cause, young-onset, and late-onset dementias than women. This association was fully mediated by health-related conditions or blood/urinary biomarkers and largely mediated by lifestyle factors. Our findings are important for understanding potential mechanisms of sex in dementia risk.
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Covariates were selected based on their known associations with Alzheimer Disease in the UK Biobank cohort.
“Covariates were selected based on their known associations with Alzheimer Disease in the UKB cohort.”
From TET2-mutant myeloid cells mitigate Alzheimer’s disease progression via CNS infiltration and enhanced phagocytosis in mice (2025) · cites this paper as [75]
The Methods > Study population section identifies age as an important determinant of dementia and explains why participants were matched by age. Methods > Statistical analysis lists factors examined as potential mediators, but does not say they were selected because of known associations with Alzheimer disease. The paper studies incident dementia rather than specifically Alzheimer disease; page numbers are unavailable in our copy. (LLM, conf=0.78)
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- Authors
- Shang, X., Roccati, E., Zhu, Z., Kiburg, K., Wang, W., Huang, Y., Zhang, X., Zhang, X., Liu, J., Tang, S., Hu, Y., Ge, Z., Yu, H., & He, M.
- Affiliations
- The Royal Melbourne Hospital (AU)
- University of Tasmania (AU)
- Centre for Eye Research Australia (AU)
- Sun Yat-sen University (CN)
- Guangdong Academy of Medical Sciences (CN)
- Monash University (AU)
- Corresponding author
- Shang, Xianwen
- Yu, Honghua
- He, Mingguang
- ORCID
- Venue
- Alzheimer's Research & Therapy
- Published
- 2023-01-09
- Volume
- 15
- Issue
- 1
- Pages
- 7-7
- ISSN
- 1758-9193 (ISSN-L)
- PMC
- PMC9827665
- OpenAlex
- W4313812418
- Cited by
- 18
- References
- 50
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 5 · 2023: 2
- FWCI
- 3.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Alzheimer s Research & Therapy (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Monash University Research Portal (Monash University) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Postdoctoral Research Funds of Guangdong Provincial People’s Hospital (BY012021047)
- High-level Talent Flexible Introduction Fund of Guangdong Provincial People’s Hospital (KJ012019530)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Sex and Gender in Healthcare
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
- Keywords
- sex differences, dementia incidence, mediation analysis, early-onset dementia, late-onset dementia, multimorbidity, apolipoprotein(a), creatinine, LDL cholesterol, biomarkers, lifestyle factors, community-dwelling adults, UK Biobank
- MeSH terms
- Adult, Aged, Dementia, Female, United Kingdom, Humans, Infant, Newborn, Male, Middle Aged, Retrospective Studies, Risk Factors, Sex Characteristics, Incidence, Biological Specimen Banks, Independent Living
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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