Pathological changes within the cerebral vasculature in Alzheimer's disease: New perspectives

Cerebrovascular disease underpins vascular dementia (VaD), but structural and functional changes to the cerebral vasculature contribute to disease pathology and cognitive decline in Alzheimer's disease (AD). In this review, we discuss the contribution of cerebral amyloid angiopathy and non-amyloid small vessel disease in AD, and the accompanying changes to the density, maintenance and remodelling of vessels (including alterations to the composition and function of the cerebrovascular basement membrane). We consider how abnormalities of the constituent cells of the neurovascular unit - particularly of endothelial cells and pericytes - and impairment of the blood-brain barrier (BBB) impact on the pathogenesis of AD. We also discuss how changes to the cerebral vasculature are likely to impair A beta clearance - both intra-periarteriolar drainage (IPAD) and transport of A beta peptides across the BBB, and how impaired neurovascular coupling and reduced blood flow in relation to metabolic demand increase amyloidogenic processing of APP and the production of A beta. We review the vasoactive properties of A beta peptides themselves, and the probable bi-directional relationship between vascular dysfunction and A beta accumulation in AD. Lastly, we discuss recent methodological advances in transcriptomics and imaging that have provided novel insights into vascular changes in AD, and recent advances in assessment of the retina that allow in vivo detection of vascular changes in the early stages of AD.

Automated summary

This review discusses the role of cerebrovascular disease in vascular dementia and Alzheimer's disease, focusing on the changes in vascular structure and function and their impact on disease pathology and cognitive decline. It highlights the contribution of cerebral amyloid angiopathy, non-amyloid small vessel disease, abnormalities in the neurovascular unit, and impairment of the blood-brain barrier to the pathogenesis of Alzheimer's disease. Furthermore, it explores how changes in the cerebral vasculature impair Aβ clearance and increase Aβ production.