Association of Regional White Matter Hyperintensities With Longitudinal Alzheimer-Like Pattern of Neurodegeneration in Older Adults
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Importance: Small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH), is associated with cognitive decline and risk of clinical Alzheimer disease (AD). One way in which small vessel cerebrovascular disease could contribute to AD is through the promotion of neurodegeneration; the effect of small vessel cerebrovascular disease on neurodegeneration may differ across racial and ethnic groups. Objective: To examine whether WMH volume is associated with cortical thinning over time and subsequent memory functioning and whether the association between WMH volume and cortical thinning differs among racial and ethnic groups. Design, Setting, and Participants: This longitudinal community-based cohort study included older adults from northern Manhattan who were participants in the Washington Heights-Inwood Columbia Aging Project. Participants underwent two 3T magnetic resonance imaging (MRI) scans a mean of 4 years apart. Data were collected from March 2011 to January 2020. Exposures: Total and regional WMH volumes. Main Outcomes and Measures: The association of total and regional WMH volumes with cortical thinning over time was tested using general linear models in a vertexwise analysis. Cortical thinning was measured vertexwise by symmetrized percent change between 2 time points. The association of changes in cortical thickness with memory and whether this association differed by race and ethnicity was also analyzed. Delayed memory was a secondary outcome. Results: In 303 participants (mean [SD] age, 73.16 [5.19] years, 181 [60%] women, 96 [32%] non-Hispanic White, 113 [37%] Non-Hispanic Black, 94 [31%] Hispanic), baseline WMH volumes were associated with cortical thinning in medial temporal and frontal/parietal regions. Specifically, total WMH volume was associated with cortical thinning in the right caudal middle frontal cortex (P = .001) and paracentral cortex (P = .04), whereas parietal WMH volume was associated with atrophy in the left entorhinal cortex (P = .03) and right rostral middle frontal (P < .001), paracentral (P < .001), and pars triangularis (P = .02) cortices. Thinning of the right caudal middle frontal and left entorhinal cortices was related to lower scores on a memory test administered closest to the second MRI visit (right caudal middle frontal cortex: standardized β = 0.129; unstandardized b = 0.335; 95% CI, 0.055 to 0.616; P = .01; left entorhinal cortex: β = 0.119; b = 0.290; 95% CI, 0.018 to 0.563; P = .03). The association of total WMH with thinning in the right caudal middle frontal and right paracentral cortex was greater in non-Hispanic Black participants compared with White participants (right caudal middle frontal cortex: β = -0.222; b = -0.059; 95% CI, -0.114 to -0.004; P = .03; right paracentral cortex: β = -0.346; b = -0.155; 95% CI, -0.244 to -0.066; P = .001). The association of parietal WMH with cortical thinning of the right rostral middle frontal, right pars triangularis, and right paracentral cortices was also stronger among non-Hispanic Black participants compared with White participants (right rostral middle frontal cortex: β = -0.252; b = -0.202; 95% CI, -0.349 to -0.055; P = .007; right pars triangularis cortex: β = -0.327; b = -0.253; 95% CI, -0.393 to -0.113; P < .001; right paracentral cortex: β = -0.263; b = -0.337; 95% CI, -0.567 to -0.107; P = .004). Conclusions and Relevance: In this study, small vessel cerebrovascular disease, operationalized as WMH, was associated with subsequent cortical atrophy in regions that overlap with typical AD neurodegeneration patterns, particularly among non-Hispanic Black older adults. Cerebrovascular disease may affect risk and progression of AD by promoting neurodegeneration and subsequent memory decline.
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The spatial distribution of WMH is differentially associated with amyloid pathology, vascular risks, and specific cognitive domains.
“The spatial distribution of WMH was found to be differentially associated with amyloid pathology, vascular risks, and specific cognitive domains. 18 , 19 , 64”
From White matter hyperintensity modulates the amyloid‐tau‐cognition association and anti‐amyloid treatment efficacy in asymptomatic older adults (2025) · cites this paper as [18]
The Introduction and Discussion (pages not provided) link parietal WMH and WMH-related cortical changes to memory and executive dysfunction. The paper does not establish differential associations between WMH location and amyloid pathology or vascular risk factors; its Discussion calls for future research on WMH and amyloid biomarkers. (LLM, conf=0.86)
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- Authors
- Rizvi, B., Lao, P. J., Chesebro, A. G., Dworkin, J. D., Amarante, E., Beato, J. M., Gutierrez, J., Zahodne, L. B., Schupf, N., Manly, J. J., Mayeux, R., & Brickman, A. M.
- Affiliations
- Columbia University (US)
- Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York
- University of Michigan (US)
- Corresponding author
- Brickman, Adam M.
- ORCID
- Venue
- JAMA Network Open
- Publisher
- American Medical Association (AMA)
- Published
- 2021-10-05
- Volume
- 4
- Issue
- 10
- Pages
- e2125166
- ISSN
- 2574-3805 (ISSN-L)
- PMC
- PMC8493439
- OpenAlex
- W3203966537
- Cited by
- 79
- References
- 59
- Citations by year
- 2026: 11 · 2025: 23 · 2024: 19 · 2023: 12 · 2022: 14
- FWCI
- 8.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- JAMA Network Open (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (RF1AG054023, R01AG054520, P30AG066462, R01AG072474)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- white matter hyperintensities, cerebral small vessel disease, cortical thinning, neurodegeneration, Alzheimer's disease, memory decline, delayed recall, racial and ethnic differences, entorhinal cortex, parietal white matter, older adults, cognitive aging
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Brain, Female, Humans, Magnetic Resonance Imaging, Male, Monte Carlo Method, New York, Neurodegenerative Diseases, White Matter
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