The role of vascular factors in Alzheimer's disease: from cerebrovascular pathological mechanisms to blood biomarkers

Alzheimer's disease (AD) is the most common dementia, and post-mortem and imaging studies consistently demonstrate that vascular pathology coexists with plaques and tangles in most AD brains. Vascular risk factors—hypertension, diabetes, dyslipidaemia, and atrial fibrillation—damage the neurovascular unit, disrupt the blood-brain barrier, and induce chronic hypoperfusion, thereby promoting β-amyloid (Aβ) deposition, tau hyperphosphorylation, and neuroinflammation. Cerebral small vessel disease, amyloid angiopathy, and carotid stenosis are overrepresented in AD and accelerate cognitive decline. Ultrasensitive blood assays now enable plasma Aβ42/40, phosphorylated tau isoforms, glial fibrillary acidic protein, and neurofilament light chain to approach the diagnostic accuracy of cerebrospinal fluid and PET, while endothelial injury markers such as vascular endothelial-cadherin and soluble adhesion molecules are emerging. Against this background, this review contends that AD diagnostics must move beyond a single-pathology framework toward an integrated model that combines neurodegenerative and vascular injury biomarkers. Reliance on Aβ and tau alone cannot capture clinical heterogeneity nor guide vascular-targeted interventions. A multidimensional blood panel reflecting pericyte loss, endothelial dysfunction, and blood-brain barrier compromise may offer improved stratification and ultimately help identify whether a biomarker-defined subgroup could benefit from vascular interventions—a hypothesis that remains to be tested prospectively. This review traverses the entire cascade from risk factors through cerebrovascular mechanisms to surgical considerations and blood biomarkers, aiming to provide a clinically actionable reference for multidisciplinary dementia care.