Potential Role of Venular Amyloid in Alzheimer's Disease Pathogenesis

Insurmountable evidence has demonstrated a strong association between Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA), along with various other cerebrovascular diseases. One form of CAA, which is the accumulation of amyloid-beta peptides (A beta) along cerebral vessel walls, impairs perivascular drainage pathways and contributes to cerebrovascular dysfunction in AD. To date, CAA research has been primarily focused on arterial A beta, while the accumulation of A beta in veins and venules were to a lesser extent. In this review, we describe preclinical models and clinical studies supporting the presence of venular amyloid and potential downstream pathological mechanisms that affect the cerebrovasculature in AD. Venous collagenosis, impaired cerebrovascular pulsatility, and enlarged perivascular spaces are exacerbated by venular amyloid and increase A beta deposition, potentially through impaired perivascular clearance. Gaining a comprehensive understanding of the mechanisms involved in venular A beta deposition and associated pathologies will give insight to how CAA contributes to AD and its association with AD-related cerebrovascular disease. Lastly, we suggest that special consideration should be made to develop A beta-targeted therapeutics that remove vascular amyloid and address cerebrovascular dysfunction in AD.