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White matter hyperintensities are a core feature of Alzheimer's disease: Evidence from the dominantly inherited Alzheimer network
Lee S, Viqar F, Zimmerman ME, Narkhede A, Tosto G, Benzinger TL, Marcus DS, Fagan AM et al.. Annals of neurology, 2016-04-27
Topic: Amyloid, tau and blood-test diagnosis
Objective White matter hyperintensities (WMHs) are areas of increased signal on T2-weighted magnetic resonance imaging (MRI) scans that most commonly reflect small vessel cerebrovascular disease. Increased WMH volume is associated with risk and progression of Alzheimer's disease (AD). These observations are typically interpreted as evidence that vascular abnormalities play an additive, independent role contributing to symptom presentation, but not core features of AD. We examined the severity and distribution of WMH in presymptomatic PSEN1, PSEN2, and APP mutation carriers to determine the extent to which WMH manifest in individuals genetically determined to develop AD. Methods The study comprised participants (n = 299; age = 39.03 ± 10.13) from the Dominantly Inherited Alzheimer Network, including 184 (61.5%) with a mutation that results in AD and 115 (38.5%) first-degree relatives who were noncarrier controls. We calculated the estimated years from expected symptom onset (EYO) by subtracting the affected parent's symptom onset age from the participant's age. Baseline MRI data were analyzed for total and regional WMH. Mixed-effects piece-wise linear regression was used to examine WMH differences between carriers and noncarriers with respect to EYO. Results Mutation carriers had greater total WMH volumes, which appeared to increase approximately 6 years before expected symptom onset. Effects were most prominent for the parietal and occipital lobe, which showed divergent effects as early as 22 years before estimated onset. Interpretation Autosomal-dominant AD is associated with increased WMH well before expected symptom onset. The findings suggest the possibility that WMHs are a core feature of AD, a potential therapeutic target, and a factor that should be integrated into pathogenic models of the disease. Ann Neurol 2016;79:929-939.
Key findings
- Increased WMH volume is associated with risk and progression of Alzheimer's disease (AD).
- Methods The study comprised participants (n = 299; age = 39.03 ± 10.13) from the Dominantly Inherited Alzheimer Network, including 184 (61.5%) with a mutation that results in AD and 115 (38.5%) first-degree relatives who were noncarrier controls.
- Results Mutation carriers had greater total WMH volumes, which appeared to increase approximately 6 years before expected symptom onset.
- Interpretation Autosomal-dominant AD is associated with increased WMH well before expected symptom onset.
Why it matters
Among 299 adults from families with inherited Alzheimer's disease, people carrying a causal mutation had more white matter hyperintensities on MRI (brain changes that usually reflect small-vessel disease) than their non-carrier relatives. The difference appeared about 6 years before their estimated symptom onset, and in the parietal and occipital lobes as early as 22 years before. The authors say this suggests the possibility that these changes are a core part of Alzheimer's rather than only a separate vascular add-on; the study used one baseline scan per person, and it reports no effect sizes and does not test whether the finding applies to common late-onset Alzheimer's.
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Study details
- Participants299
- Effect size61.5%; 38.5%
- Evidence strengthLow
How this study scored 63/100
Published in a leading specialty journal. Scored zero for study design and randomised / blinded because the record does not state it. We have no data on senior author's track record, so that was left out: it earned 60 of the 96 points we could judge it on, which is 63 out of 100.
| 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 | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2016 — within 20 year(s) of the newest study here |
| Sample size | 2 / 4 | 299 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 | 6 / 7 | Cited 544 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 45.3 citations a year over 12 year(s) since 2016 |
| Impact for its field and year | 5 / 6 | Cited 30.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 40 other studies in this library |
| Still being cited | 3 / 4 | Cited 159 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | 2 / 3 | Massachusetts General Hospital: institution h-index 2,057 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 30 institution(s) in 4 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 27016429) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 60 / 96 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 60 of the 96 points we could judge it on is 63 out of 100. |
| Total | 63 / 100 | — |
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Read the original
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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
Lee, S., Viqar, F., Zimmerman, M. E., Narkhede, A., Tosto, G., Benzinger, T. L., et al. (2016). White matter hyperintensities are a core feature of Alzheimer's disease: Evidence from the dominantly inherited Alzheimer network. Annals of neurology. https://doi.org/10.1002/ana.24647
Vancouver
Lee S, Viqar F, Zimmerman ME, Narkhede A, Tosto G, Benzinger TL, et al. White matter hyperintensities are a core feature of Alzheimer's disease: Evidence from the dominantly inherited Alzheimer network. Annals of neurology. 2016. doi:10.1002/ana.24647. PMID: 27016429.
BibTeX
@article{lee2016-27016429,
author = {Lee, S. and Viqar, F. and Zimmerman, M. E. and Narkhede, A. and Tosto, G. and Benzinger, T. L. and Marcus, D. S. and Fagan, A. M. and others},
title = {{White matter hyperintensities are a core feature of Alzheimer's disease: Evidence from the dominantly inherited Alzheimer network}},
journal = {Annals of neurology},
year = {2016},
doi = {10.1002/ana.24647},
pmid = {27016429},
url = {https://doi.org/10.1002/ana.24647}
}
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