Extracranial Vascular Arterial Stiffness Contributes to Cerebral Small Vessel Disease, Stroke, and Late‐Onset Alzheimer’s Disease

Abstract Cerebrocardiovascular diseases including coronary artery disease, ischemic heart disease, and stroke are the number one cause of global mortality. Structural and functional properties of the vascular arterial wall play an important role in the development and progression of extracranial vascular arterial stiffness (VAS). VAS has emerged as a marker of risk for aging, dementia, vascular contributions to impaired cognition and dementia (VCID), stroke (ischemic and hemorrhagic), misfolded proteins (amyloid beta and tau) deposition, neurodegeneration, brain atrophy, and late-onset Alzheimer’s disease. VAS is associated with increased oxidative redox stress, inflammation, vascular remodeling and calcification, increased pulse wave velocity with increased pulsatile pulse pressure, and systolic hypertension, which serve as part of the multiple injurious stimuli to vulnerable neurovascular unit capillary endothelial cells with high flow and low resistance. Notably, advancing age, hypertension, atherosclerosis, and vascular calcification are the most common causes of VAS. VAS contributes to cerebral small vessel disease (SVD) and chronic cerebral hypoperfusion that is capable of instigating neurodegeneration, brain atrophy, and late onset Alzheimer’s disease. This narrative review discusses the evidence that links VAS and SVD to brain structural and functional abnormalities via a heart, vessel, brain axis, which leads to SVD, neurodegeneration, brain atrophy, impaired cognition, and late-onset Alzheimer’s disease. Indeed, VAS has emerged as an important marker of risk for accelerated brain aging and dementia through its associations with SVD, stroke, chronic cerebral hypoperfusion, amyloid beta plaques and tau neurofibrillary tangle deposition, brain atrophy, cognitive impairment, and late-onset Alzheimer’s disease.