Association of small vessel disease with tau pathology
Open accessAbstract
Emerging evidence suggests that small vessel disease (SVD) is a risk factor for clinical dementia and may contribute to AD neuropathological changes. Watershed brain regions are located at the most distal areas between arterial territories, making them vulnerable to SVD-related changes. We examined the association of pathologic markers of SVD, specifically arteriolosclerosis in watershed brain regions, with AD pathologic changes. Participants ( N = 982; mean age-at-death = 90; 69% women) were enrolled as part of one of two cohort studies of aging and dementia. At autopsy, neuropathological evaluation included semi-quantitative grading of arteriolosclerosis pathology from 2 cortical watershed regions: the anterior watershed (AWS) and posterior watershed (PWS), densities for cortical β-amyloid and tau-tangle pathology, and other common age-related pathologies. Linear regression models examined the association of watershed arteriolosclerosis pathology with β-amyloid and tau-tangle burden. In follow-up analyses, available ex-vivo MRI and proteomics data in a subset of decedents were leveraged to examine the association of whole brain measure of WMH, as a presumed MRI marker of SVD, with β-amyloid and tau-tangle burden, as well as to examine the association of watershed arteriolosclerosis with proteomic tau. Watershed arteriolosclerosis was common, with 45% of older persons having moderate-to-severe arteriolosclerosis pathology in the AWS region, and 35% in the PWS. In fully adjusted models that controlled for demographics and common age-related pathologies, an increase in severity of PWS arteriolosclerosis was associated with a higher burden of tau-tangle burden, specifically neocortical tau burden, but not with β-amyloid. AWS arteriolosclerosis was not associated with β-amyloid or tau pathology. Ex-vivo WMH was associated with greater tau-tangle pathology burden but not β-amyloid. Furthermore, PWS arteriolosclerosis was associated with higher abundance of tau phosphopeptides, that promote formation of tau aggregates. These data provide compelling evidence that SVD, specifically posterior watershed arteriolosclerosis pathology, is linked with tau pathological changes in the aging brain.
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More severe arteriolosclerosis in the posterior watershed region and higher whole-brain WMH are associated with tau tangle burden but not Aβ.
“Using autopsy data from 982 cases, Kapasi et al. showed that more severe arteriolosclerosis in the posterior watershed region and higher whole‐brain WMH were associated with tau tangle burden but not Aβ. 39”
From White matter hyperintensity modulates the amyloid‐tau‐cognition association and anti‐amyloid treatment efficacy in asymptomatic older adults (2025) · cites this paper as [39]
Tau pathology may represent a convergent pathway in AD, with vascular pathology being one of several contributing factors.
“Therefore, tau pathology may represent a convergent pathway in AD, with vascular pathology being one of several contributing factors. 39”
From White matter hyperintensity modulates the amyloid‐tau‐cognition association and anti‐amyloid treatment efficacy in asymptomatic older adults (2025) · cites this paper as [39]
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“We conceptualize that SVD may be associated with tau phosphorylation through several downstream biological processes, including but not limited to neuroinflammation and oxidative stress associated with blood–brain barrier (BBB) dysfunction, which could impact key pathways that regulate intrinsic neuronal/cellular acti…”
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Role of the transcription factor NRF2 in maintaining the integrity of the Blood-Brain Barrier
Cazalla, E., Cuadrado, A., & García‐Yagüe, Á. J. (2024) · Fluids and Barriers of the CNS · doi:10.1186/s12987-024-00599-5 · Cited by 36 · see citing works
Cogswell, P. M., Lundt, E. S., Therneau, T. M., Mester, C. T., Wiste, H. J., Graff‐Radford, J., Schwarz, C. G., Senjem, M. L., Gunter, J. L., Reid, R. I., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-38878-8 · Cited by 29 · see citing works
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Current and Future Treatments of Vascular Cognitive Impairment
Ip, B. Y. M., Ko, H., Lam, B. Y. K., Au, L. W. C., Lau, A. Y. L., Huang, J., Kwok, A. J., Leng, X., Cai, Y., Leung, T. W. H., et al. (2024) · Stroke · doi:10.1161/strokeaha.123.044174 · Cited by 26 · see citing works
Oveisgharan, S., Kim, N., Agrawal, S., Yu, L., Leurgans, S. E., Kapasi, A., Arfanakis, K., Bennett, D. A., Schneider, J. A., & Buchman, A. S. (2022) · Acta Neuropathologica · doi:10.1007/s00401-022-02527-z · Cited by 24 · see citing works
Self-citationNewton, P., the BIOCARD Research Team, Tchounguen, J., Pettigrew, C., Lim, C., Lin, Z., Lu, H., Moghekar, A., Albert, M., & Soldan, A. (2023) · Journal of Alzheimer's Disease · doi:10.3233/jad-220846 · Cited by 23 · see citing works
Brickman, A. M., & Rizvi, B. M. (2023) · Alzheimer s & Dementia · doi:10.1002/alz.13371 · Cited by 21 · see citing works
Rizvi, B. M., Sathishkumar, M. T., Kim, S., Márquez, F., Granger, S. J., Larson, M. S., Miranda, B. A., Hollearn, M. K., McMillan, L. C., Nan, B., et al. (2022) · NeuroImage Clinical · doi:10.1016/j.nicl.2022.103308 · Cited by 18 · see citing works
Vollhardt, A., Frölich, L., Stockbauer, A., Danek, A., Schmitz, C., & Wahl, A.-S. (2025) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.106845 · Cited by 17 · see citing works
Cortical tau deposition promotes atrophy in connected white matter regions in Alzheimer’s disease
Pescoller, J., Dewenter, A., Dehsarvi, A., Steward, A., Frontzkowski, L. K., Zhu, Z., Roemer, S. N., Palleis, C., Hirsch, F., Wagner, F., et al. (2025) · Brain · doi:10.1093/brain/awaf339 · Cited by 15 · see citing works
The comorbidity and co-medication profile of patients with progressive supranuclear palsy
Greten, S., Wegner, F., Jensen, I., Krey, L., Rogozinski, S., Fehring, M., Heine, J., Doll‐Lee, J., Pötter‐Nerger, M., Zeitzschel, M., et al. (2023) · Journal of Neurology · doi:10.1007/s00415-023-12006-4 · Cited by 14 · see citing works
Atherosclerosis and Hippocampal Volumes in Older Adults: The Role of Age and Blood Pressure
Kapasi, A., Capuano, A. W., Lamar, M., Leurgans, S. E., Evia, A. M., Bennett, D. A., Arfanakis, K., & Schneider, J. A. (2024) · Journal of the American Heart Association · doi:10.1161/jaha.123.031551 · Cited by 14 · see citing works
Self-citationWhite Matter Hyperintensity as a Vascular Contribution to the AT(N) Framework
Ng, K. P., shen, J., Chiew, H. J., Ng, A., Kandiah, N., Rosa‐Neto, P., & Gauthier, S. G. (2023) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2023.53 · Cited by 12 · see citing works
Arvanitakis, Z., Capuano, A. W., Tong, H., Mehta, R. I., Anokye‐Danso, F., Bennett, D. A., Arnold, S. E., & Ahima, R. S. (2024) · Annals of Neurology · doi:10.1002/ana.26882 · Cited by 13 · see citing works
Self-citationAssociation of Stroke and Cerebrovascular Pathologies With Scam Susceptibility in Older Adults
Kapasi, A., Schneider, J. A., Yu, L., Lamar, M., Bennett, D. A., & Boyle, P. A. (2022) · JAMA Neurology · doi:10.1001/jamaneurol.2022.3711 · Cited by 13 · see citing works
Self-citationSilbert, L. C. (2024) · CONTINUUM Lifelong Learning in Neurology · doi:10.1212/con.0000000000001508 · Cited by 11 · see citing works
Wang, H.-P., Scalco, R., Saito, N. H., Beckett, L. A., Nguyen, M.-L., Huie, E. Z., Honig, L. S., DeCarli, C. S., Rissman, R. A., Teich, A. F., et al. (2024) · Acta Neuropathologica Communications · doi:10.1186/s40478-024-01773-4 · Cited by 9 · see citing works
Traumatic Brain Injury and Alzheimer’s Disease: A Shared Neurovascular Hypothesis
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Jones, A. A., Ramos‐Miguel, A., Gicas, K. M., Petyuk, V., Leurgans, S. E., Jager, P. L. D., Schneider, J. A., Bennett, D., Honer, W. G., & Casaletto, K. B. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14286 · Cited by 7 · see citing works
Self-citationXiao, Y., Chen, S., Zhang, Z., Huang, J., Gui, Y., Luo, D., Deng, X., Dai, J., & Xiao, X. (2024) · Quantitative Imaging in Medicine and Surgery · doi:10.21037/qims-24-151 · Cited by 6 · see citing works
Lamar, M., Arfanakis, K., Yu, L., Kapasi, A., Han, S. D., Fleischman, D. A., Bennett, D. A., & Boyle, P. A. (2023) · American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2023.07.008 · Cited by 5 · see citing works
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Self-citationCerebrovascular Pathology and Cognitive Outcomes in Older Black Decedents
Kapasi, A., Capuano, A. W., Mojdeganlou, P., Bennett, D. A., Lamar, M., Leurgans, S. E., Schneider, J. A., & Barnes, L. L. (2025) · Stroke · doi:10.1161/strokeaha.124.047954 · Cited by 4 · see citing works
Self-citationRelationship of antihypertensives with late‐life cognitive decline and neuropathology
Sood, A., Capuano, A. W., Mehta, R. I., Barnes, L. L., Bennett, D. A., & Arvanitakis, Z. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70739 · Cited by 4 · see citing works
Self-citationNeurologic Effects of SARS-CoV-2 Transmitted among Dogs
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Small vessel disease burden and functional brain connectivity in mild cognitive impairment
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Complex relationships of socioeconomic status with vascular and Alzheimer’s pathways on cognition
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Self-citationCerebral amyloid angiopathy and Alzheimer's and related pathologies across APOE genotypes
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Self-citationOnset ages of cerebrovascular disease and amyloid and effects on cognition in risk-enriched cohorts
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Using gut neuron health as a predictive indicator of neurodegenerative disease
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Pathologic subtyping of Alzheimer’s disease brain tissue reveals disease heterogeneityPreprint
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Small vessel disease promotes tau tangles
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Towards in vivo MRI-based diagnostics and tracking of dementia
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Small vessel disease: Trigger or bystander of late-onset epilepsy of unknown origin?
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Medial temporal lobe atrophy is associated with age and pathologies, especially small vessel disease
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Self-citationBlood Pressure Variability and Alzheimer Disease Biomarkers
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- Authors
- Kapasi, A., Yu, L., Petyuk, V., Arfanakis, K., Bennett, D. A., & Schneider, J. A.
- Affiliations
- Rush University Medical Center (US)
- Pacific Northwest National Laboratory (US)
- Corresponding author
- Kapasi, Alifiya
- Venue
- Acta Neuropathologica
- Published
- 2022-01-19
- Volume
- 143
- Issue
- 3
- Pages
- 349-362
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC8858293
- OpenAlex
- W4205375426
- Cited by
- 55
- References
- 71
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 18 · 2023: 11 · 2022: 5
- FWCI
- 7.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Acta Neuropathologica (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- national institute on aging (R01AG017917, P30AG010161, R01AG015819)
- national institute of neurological disorders and stroke (UH3NS100599)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
- Keywords
- cerebral small vessel disease, arteriolosclerosis, tau pathology, amyloid-beta, white matter hyperintensities, Alzheimer's disease pathology, brain aging, dementia risk
- MeSH terms
- Aged, Aged, 80 and over, Aging, Alzheimer Disease, Brain, Female, Humans, Male, Amyloid beta-Peptides, tau Proteins, Proteomics
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