| Title: | Additive Effects of White Matter Hyperintensity and APOE ε4 Status on Risk of Incident Dementia in Two Large Longitudinal Cohorts |
| Journal: | Annals of Neurology |
| Published: | 21 Nov 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41267647/ |
| DOI: | https://doi.org/10.1002/ana.78103 |
| URL: | https://pmc.ncbi.nlm.nih.gov/articles/PMC12967297/ |
Publication 18845
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
OBJECTIVE: To evaluate whether white matter hyperintensities (WMH) and apolipoprotein E (APOE) ε4 status have an additive or multiplicative effect on the risk of incident all-cause dementia.</p>
METHODS: We conducted a prospective cohort study in the Atherosclerosis Risk in Communities (ARIC) study and confirmed findings in the UK Biobank (UKB). The exposures were APOE ε4 status (0 vs. ≥1 allele) and WMH on magnetic resonance imaging (MRI). The primary outcome was incident all-cause dementia. After confirming an additive interaction, we created combined exposure groups: WMH-/ε4-, WMH+/ε4-, WMH-/ε4+, and WMH+/ε4+. Cox proportional hazards models were adjusted for age, sex, race, education, cognition (ARIC only), hypertension, diabetes, and prior stroke.</p>
RESULTS: In ARIC (n = 1,736, mean age 63, 58.8% female, 48.7% non-Hispanic White individuals, median follow-up 18.6 years), the dementia incidence rate was 10.4 (95% CI, 9.2-11.6) per 1,000 person-years. Compared to WMH-/ε4-, adjusted hazard ratios (HRs) for dementia were: WMH-/ε4+, 1.5 (95% CI, 1.1-2.1); WMH+/ε4-, 2.0 (95% CI, 1.4-2.7); and WMH+/ε4+, 3.2 (95% CI, 2.2-4.6). In UKB (n = 40,307, mean age 55, 52.7% female, 97.1% non-Hispanic White individuals, median follow-up 3.2 years), the dementia incidence rate was 0.42 (95% CI, 0.32-0.55) per 1,000 person-years. Adjusted HRs were: WMH-/ε4+, 2.3 (95% CI, 1.2-4.5); WMH+/ε4-, 2.1 (95% CI, 1.0-4.6); and WMH+/ε4+, 6.7 (95% CI, 3.2-13.9).</p>
INTERPRETATION: WMH burden and APOE ε4 status additively increase dementia risk. These findings support the potential benefit of vascular risk management to reduce WMH and delay dementia onset, even among genetically at-risk individuals. ANN NEUROL 2026;99:656-667.</p>
14 Keywords
- Aged
- Apolipoprotein E4
- Cohort Studies
- Dementia
- Female
- Humans
- Incidence
- Longitudinal Studies
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Prospective Studies
- Risk Factors
- White Matter
16 Authors
- Adam de Havenon
- Lauren Littig
- Santiago Clocchiatti-Tuozzo
- Ian P Johnson
- Sofia Constantinescu
- Cyprien A Rivier
- Shufan Huo
- William T Kimberly
- Teresa Gomez-Isla
- Yvonne Kim
- Eric Stulberg
- Eric E Smith
- Jonathan Rosand
- Guido Falcone
- Kevin N Sheth
- Adam M Brickman
1 Application
| Application ID | Title |
|---|---|
| 58743 | Genetic and non-genetic determinants of cardiovascular disease, cerebrovascular disease, and aging. |
Enabling scientific discoveries that improve human health