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Additive Effects of White Matter Hyperintensity and APOE ε4 Status on Risk of Incident Dementia in Two Large Longitudinal Cohorts
Adam de Havenon, Lauren Littig, Santiago Clocchiatti‐Tuozzo, Ian P Johnson, Sofia Constantinescu, Cyprien A. Rivier, Shufan Huo, William Taylor Kimberly et al.. Annals of Neurology, 2025-11-21
Topic: Amyloid, tau and blood-test diagnosis
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). 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.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
de Havenon, A., Littig, L., Clocchiatti‐Tuozzo, S., Johnson, I. P., Constantinescu, S., Rivier, C. A., et al. (2025). Additive Effects of White Matter Hyperintensity and APOE ε4 Status on Risk of Incident Dementia in Two Large Longitudinal Cohorts. Annals of Neurology. https://doi.org/10.1002/ana.78103
Vancouver
de Havenon A, Littig L, Clocchiatti‐Tuozzo S, Johnson IP, Constantinescu S, Rivier CA, et al. Additive Effects of White Matter Hyperintensity and APOE ε4 Status on Risk of Incident Dementia in Two Large Longitudinal Cohorts. Annals of Neurology. 2025. doi:10.1002/ana.78103. PMID: 41267647.
BibTeX
@article{dehavenon2025-41267647,
author = {de Havenon, Adam and Littig, Lauren and Clocchiatti‐Tuozzo, Santiago and Johnson, Ian P and Constantinescu, Sofia and Rivier, Cyprien A. and Huo, Shufan and Kimberly, William Taylor and others},
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},
year = {2025},
doi = {10.1002/ana.78103},
pmid = {41267647},
url = {https://doi.org/10.1002/ana.78103}
}
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Key findings
- 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).
- WMH burden and APOE ε4 status additively increase dementia risk.
Why it matters
In two large longitudinal cohorts, white matter hyperintensity burden and APOE ε4 status each increased dementia risk, and having both raised risk further. The authors say these findings support the potential benefit of vascular risk management to reduce white matter hyperintensities and delay dementia onset, even in people genetically at risk.
Study details
- Study designcohort study
- Participants1,736
- Effect size58.8%; 48.7%; 52.7%
- Evidence strengthModerate
How this study scored 57/100
Published in a leading specialty journal, and it is a cohort study following people over time. Scored zero for randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Annals of Neurology) |
| Journal's citation record | 3 / 4 | Annals of Neurology: journal h-index 437 (OpenAlex, 2026-10-29) |
| Study design | 7 / 12 | A cohort study following people over time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 3 / 4 | 1,736 participants |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| 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 | 1 / 7 | Cited 1 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 1 / 6 | Cited 0.6× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 1 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Adam M. Brickman: h-index 87 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Massachusetts General Hospital: institution h-index 2,057 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 6 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41267647) |
| Free to read | 2 / 2 | Free to read |
| Total | 57 / 100 | — |
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