Abstract
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.
Highlights
Cerebral small vessel disease (SVD) is one of the most common causes of vascular cognitive impairment and dementia
We extend these findings, indicating that watershed arteriosclerosis pathology is associated with proteomic tau phosphopeptides
Our current study extends these findings by showing that watershed arteriolosclerosis, posterior watershed, is associated with greater tau-tangle pathology burden and higher abundance of tau phosphorylation epitopes
Summary
Cerebral small vessel disease (SVD) is one of the most common causes of vascular cognitive impairment and dementia. We and others have shown that majority of older persons diagnosed with Alzheimer’s dementia have one or more vascular pathologies, highlighting a central role of cerebrovascular disease in cognitive aging pathogenesis. Cerebral hypoperfusion is a well-established phenotype in patients with AD, a predictor of cognitive decline, and emerging as a candidate biomarker for dementia risk [15, 21] While it remains unclear whether hypoperfusion in AD is a cause or consequence of disease pathogenesis, accumulating evidence suggests an intertwined relationship between cerebral blood flow, β-amyloid, and tau. Overall vascular risk burden score was quantified as ‘ever present’ if participant ever reported diabetes, hypertension, or smoking during the
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