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White matter hyperintensities are a core feature of Alzheimer’s disease: evidence from the dominantly inherited Alzheimer network
Open accessAbstract
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.
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“findings from previous studies have also shown that WMHs often occur prior to the presence of amyloid-β plaques in preclinical AD [19,20,21]”
From Amyloid-PET and White Matter Hyperintensities Have Independent Effects on Baseline Cognitive Function and Synergistic Effects on Longitudinal Executive Function (2023) · cites this paper as [19]
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“Emerging evidence suggests that white matter microstructural changes may be not only a marker of small vessel injury but also directly related to AD pathology. 53 , 54”
From White matter hyperintensity modulates the amyloid‐tau‐cognition association and anti‐amyloid treatment efficacy in asymptomatic older adults (2025) · cites this paper as [53]
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“WMHs are considered an MRI detectable marker of white matter changes due to microvascular pathology, and are increased in autosomal-dominant Alzheimer’s disease (Lee et al., 2016).”
From White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer’s disease (2018) · cites this paper as Lee et al., 2016
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Metadata
- Authors
- Lee, S., Viqar, F., Zimmerman, M. E., Narkhede, A., Tosto, G., Benzinger, T. L. S., Marcus, D. S., Fagan, A. M., Goate, A., Fox, N. C., Cairns, N. J., Holtzman, D. M., Buckles, V., Ghetti, B., McDade, E., Martins, R. N., Saykin, A. J., Masters, C. L., Ringman, J. M., Ryan, N. S., Förster, S., Laske, C., Schofield, P. R., Sperling, R. A., Salloway, S., Correia, S., Jack, C., Weiner, M., Bateman, R. J., Morris, J. C., Mayeux, R., Brickman, A. M., & for the Dominantly Inherited Alzheimer Network
- Affiliations
- New York State Psychiatric Institute (US)
- Fordham University (US)
- Albert Einstein College of Medicine (US)
- Columbia University Irving Medical Center (US)
- NewYork–Presbyterian Hospital (US)
- Washington University in St. Louis (US)
- Icahn School of Medicine at Mount Sinai (US)
- UCL Queen Square Institute of Neurology (GB)
- Indiana University Indianapolis (US)
- Edith Cowan University (AU)
- The University of Melbourne (AU)
- University of Southern California (US)
- German Center for Neurodegenerative Diseases (DE)
- UNSW Sydney (AU)
- Brigham and Women's Hospital (US)
- Brown University (US)
- Mayo Clinic (US)
- San Francisco VA Medical Center (US)
- Corresponding author
- Brickman, Adam M.
- ORCID
- Lee, Seonjoo
- Zimmerman, Molly E.
- Tosto, Giuseppe
- Benzinger, Tammie L.S.
- Marcus, Daniel S.
- Fagan, Anne M.
- Goate, Alison
- Fox, Nick C.
- Holtzman, David M.
- Ghetti, Bernardino
- McDade, Eric
- Martins, Ralph N.
- Saykin, Andrew J.
- Masters, Colin L.
- Ringman, John M.
- Ryan, Natalie S.
- Förster, Stefan
- Laske, Christoph
- Schofield, Peter R.
- Sperling, Reisa A.
- Salloway, Stephen
- Correia, Stephen
- Jack, Clifford
- Weiner, Michael
- Bateman, Randall J.
- Morris, John C.
- Mayeux, Richard
- Brickman, Adam M.
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2016-04-27
- Volume
- 79
- Issue
- 6
- Pages
- 929-939
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC4884146
- OpenAlex
- W2309640507
- Cited by
- 542
- References
- 51
- Citations by year
- 2026: 49 · 2025: 58 · 2024: 53 · 2023: 68 · 2022: 65 · 2021: 65 · 2020: 66 · 2019: 46 · 2018: 38 · 2017: 25 · 2016: 8
- FWCI
- 34.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UNSWorks (UNSW Sydney) (submittedVersion, cc-by-nc-nd)
- Australasian Journal of Paramedicine (submittedVersion)
- Deep Blue (University of Michigan) (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- DZNE Pub (submittedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Purdue University Indianapolis (Indiana University) (submittedVersion)
- PMC
- Funders
- NIH/NIA (U19 AG032438, AG051348)
- NIHR Queen Square Dementia BRU
- German Center for Neurodegenerative Diseases (DZNE)
- Brain Exit Foundation Fellowship
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Cerebrovascular and genetic disorders
- Keywords
- white matter hyperintensities, Alzheimer's disease, autosomal dominant Alzheimer's disease, presymptomatic carriers, presenilin 1, presenilin 2, APP, cerebral small vessel disease, genetic risk
- MeSH terms
- Adult, Alzheimer Disease, Female, Heterozygote, Humans, Magnetic Resonance Imaging, Male, Peptide Fragments, Biomarkers, Case-Control Studies, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, tau Proteins, Genetic Predisposition to Disease, Presenilin-1, Presenilin-2, Young Adult, Neuroimaging, White Matter
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