Alzheimer's Disease as a Consequence of Vascular Endothelial Dysfunction
Continued efforts to clear amyloid-β in the brain have failed produce significant benefits in Alzheimer's disease patients. This has led to a great deal of theorizing, researchers proposing other disease mechanisms, or different interpretations of the relevance of amyloid-β to the development of neurodegeneration. Most of these hypotheses will be wrong, but that doesn't prevent them from being interesting reading. One class of alternative views of Alzheimer's disease involves placing an increased emphasis on vascular dysfunction in the development of the condition, and the paper here is an example of the type.
Alzheimer's disease (AD) is the most common cause of dementia, accounting for over 70% of dementia cases in individuals above the age of 65 years. The two main pathological hallmarks of AD are extracellular deposits of the amyloid-β (Aβ) protein in the form of amyloid plaques and intracellular aggregates of hyperphosphorylated tau protein in the form of neurofibrillary tangles. Current disease models are based on the notion that abnormal protein aggregation is the primary event in AD, which begins a decade or longer prior to symptom onset, and ultimately leads to synaptic injury and neurodegeneration.
Vascular disease, including arteriolosclerosis, atherosclerosis, microinfarcts, and cerebral amyloid angiopathy (CAA), is a common co-pathology which is observed in 20-80% of AD brains at autopsy. Furthermore, almost all AD brains display evidence of endothelial and capillary degeneration even in the absence of other forms of macrovascular pathology. Significant and bidirectional interactions between AD and various forms of vascular pathology have been well documented; amyloid and tau toxicity disrupts the blood-brain barrier (BBB) and alters vascular permeability, and structural or functional damage to cerebral vasculature impairs amyloid clearance and promotes tau aggregation.
Previous neuropathological studies examining vascular pathology in AD have focused primarily on pathology within the small- and medium-sized arteries and arterioles; however, there is growing evidence to suggest that "micro"-vascular disease (i.e., at the capillary level) and alterations to specific vascular constituents, such as endothelium and pericytes, play an important role in AD pathogenesis. Impaired cerebral blood flow (CBF) is a common and early predictor of AD pathology, which possibly precedes abnormal protein aggregation and directly contributes to neuronal and synaptic loss in even the earliest pre-symptomatic stages of the disease. These observations support the notion that the onset of AD may be primarily influenced by vascular, rather than neurodegenerative, mechanisms and emphasize the importance of further investigations into the vascular hypothesis of AD.