Association of small vessel disease with tau pathology

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.

Regional White Matter Hyperintensities and Alzheimer’s Disease Biomarkers Among Older Adults with Normal Cognition and Mild Cognitive Impairment

“…In this view, chronic hypoperfusion and resulting ischemia of temporal white matter regions would result in the demyelination of axons, axonal degeneration, and ultimately tangle formation [ 51 ]. This would be consistent with recent neuropathological findings that higher tangle pathology is associated with both greater small-vessel disease burden in posterior brain regions (measured by arteriosclerosis [ 52 ]) and with higher global WMH among older adults across the clinical spectrum of AD [ 52, 53 ]. Further supporting this view, a mouse model of ischemia demonstrated that hypoperfusion can promote higher phosphorylated and total tau accumulation [ 53 ].…”

The prevalence, correlation, and co-occurrence of neuropathology in old age: harmonisation of 12 measures across six community-based autopsy studies of dementia

“…Our data showed that Alzheimer's disease neuropathology and vascular pathology were largely uncorrelated. Although a few published studies have found that atherosclerosis and arteriolosclerosis are associated with Alzheimer's disease neuropathologies, 27 , 28 results from most previous autopsy cohorts align with our findings. 29 , 30 In the context of existing evidence on vascular contributions to Alzheimer's disease, 31 , 32 , 33 , 34 findings suggest that vascular and Alzheimer's disease pathways might have independent causes, but interact synergistically to accelerate and promote cognitive decline and dementia.…”

White matter hyperintensities and Alzheimer's disease: An alternative view of an alternative hypothesis

“…While one interpretation could be that WMH reflect Wallerian-like degeneration, an equally feasible interpretation is that the vascular damage caused by subtle hypoperfusion or other vascular drivers of WMH give rise or cause tau pathology and neurodegeneration observed in AD. 2 We tested this idea experimentally in a murine model…”