Dissecting the Contribution of Vascular Alterations and Aging to Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive decline that afflicts as many as 45 % of individuals who survive past the age of 85. AD has been associated with neurovascular dysfunction and brain accumulation of amyloid-β peptide, as well as tau phosphorylation and neurodegeneration, but the pathogenesis of the disease is still somewhat unclear. According to the amyloid cascade hypothesis of AD, accumulation of amyloid-β peptide (Aβ) aggregates initiates a sequence of events leading to neuronal injury and loss, and dementia. Alternatively, the vascular hypothesis of AD incorporates the vascular contribution to the disease, stating that a primary insult to brain microcirculation (e.g., stroke) not only contributes to amyloidopathy but initiates a non-amyloidogenic pathway of vascular-mediated neuronal dysfunction and injury, which involves blood-brain barrier compromise, with increased permeability of blood vessels, leakage of blood-borne components into the brain, and, consequently, neurotoxicity. Vascular dysfunction also includes a diminished brain capillary flow, causing multiple focal ischemic or hypoxic microinjuries, diminished amyloid-β clearance, and formation of neurotoxic oligomers, which lead to neuronal dysfunction. Here we present and discuss relevant findings on the contribution of vascular alterations during aging to AD, with the hope that a better understanding of the players in the "orchestra" of neurodegeneration will be useful in developing therapies to modulate the "symphony".