White matter hyperintensities: relationship to amyloid and tau burden
Open accessAbstract
Although white matter hyperintensities have traditionally been viewed as a marker of vascular disease, recent pathology studies have found an association between white matter hyperintensities and Alzheimer’s disease pathologies. The objectives of this study were to investigate the topographic patterns of white matter hyperintensities associated with Alzheimer’s disease biomarkers measured using PET. From the population-based Mayo Clinic Study of Aging, 434 participants without dementia (55% male) with FLAIR and gradient recall echo MRI, tau-PET (AV-1451) and amyloid-PET scans were identified. A subset had cerebral microbleeds detected on T2* gradient recall echo scans. White matter hyperintensities were semi-automatically segmented using FLAIR MRI in participant space and normalized to a custom template. We used statistical parametric mapping 12-based, voxel-wise, multiple-regression analyses to detect white matter hyperintense regions associated with Alzheimer’s biomarkers (global amyloid from amyloid-PET and meta-regions of interest tau uptake from tau-PET) after adjusting for age, sex and hypertension. For amyloid associations, we additionally adjusted for tau and vice versa. Topographic patterns of amyloid-associated white matter hyperintensities included periventricular white matter hyperintensities (frontal and parietal lobes). White matter hyperintense volumes in the detected topographic pattern correlated strongly with lobar cerebral microbleeds (P < 0.001, age and sex adjusted Cohen’s d = 0.703). In contrast, there were no white matter hyperintense regions significantly associated with increased tau burden using voxel-based analysis or region-specific analysis. Among non-demented elderly, amyloid load correlated with a topographic pattern of white matter hyperintensities. Further, the amyloid-associated, white matter hyperintense regions strongly correlated with lobar cerebral microbleeds suggesting that cerebral amyloid angiopathy contributes to the relationship between amyloid and white matter hyperintensities. The study did not support an association between increased tau burden and white matter hyperintense burden.
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Most cross-sectional studies reported an association between WMH and amyloid markers (CSF Aβ42 or Aβ PET) but not tau markers.
“Most cross‐sectional studies reported an association between WMH and amyloid markers (either CSF Aβ42 or Aβ deposition on PET) but not tau markers. 55 , 56 , 57 , 58 , 59”
From White matter hyperintensity modulates the amyloid‐tau‐cognition association and anti‐amyloid treatment efficacy in asymptomatic older adults (2025) · cites this paper as [57]
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- Authors
- Graff-Radford, J., Arenaza-Urquijo, E. M., Knopman, D. S., Schwarz, C. G., Brown, R. D., Rabinstein, A. A., Gunter, J. L., Senjem, M. L., Przybelski, S. A., Lesnick, T., Ward, C., Mielke, M. M., Lowe, V. J., Petersen, R. C., Kremers, W. K., Kantarci, K., Jack, C. R., & Vemuri, P.
- Affiliations
- Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA
- Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA
- Mayo Clinic (US)
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-06-14
- Volume
- 142
- Issue
- 8
- Pages
- 2483-2491
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC6658846
- OpenAlex
- W2952824079
- Cited by
- 253
- References
- 32
- Citations by year
- 2026: 25 · 2025: 43 · 2024: 39 · 2023: 38 · 2022: 46 · 2021: 34 · 2020: 27 · 2019: 1
- FWCI
- 21.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Brain (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (R37 AG011378, K76 AG057015, R01 AG041851, U01 AG006786, R01 AG034676, R01 AG56366)
- National Institute of Neurologic Disorders and Stroke (R01 NS097495)
- GHR Foundation
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
- Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Keywords
- white matter hyperintensities, amyloid burden, tau burden, Alzheimer's disease, cerebral microbleeds, cerebral amyloid angiopathy, periventricular white matter hyperintensities, tau PET, amyloid PET, FLAIR MRI, topographic patterns, non-demented elderly, Mayo Clinic Study of Aging
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Brain, Cerebral Hemorrhage, Female, Humans, Male, Middle Aged, Amyloid beta-Peptides, Cerebral Amyloid Angiopathy, tau Proteins, Positron-Emission Tomography, Neuroimaging, White Matter
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