Neurovascular dysfunction and vascular amyloid accumulation as early events in Alzheimer's disease

Alzheimer's disease (AD) is clinically characterized by a progressive loss of cognitive functions and short-term memory. AD patients present two distinctive neuropathological lesions: neuritic plaques and neurofibrillary tangles (NFTs), constituted of beta-amyloid peptide (A beta) and phosphorylated and truncated tau proteins. A beta deposits around cerebral blood vessels (cerebral amyloid angiopathy, CAA) is a major contributor to vascular dysfunction in AD. Vascular amyloid deposits could be early events in AD due to dysfunction in the neurovascular unit (NVU) and the blood-brain barrier (BBB), deterioration of the gliovascular unit, and/or decrease of cerebral blood flow (CBF). These pathological events can lead to decreased A beta clearance, facilitate a neuroinflammatory environment as well as synaptic dysfunction and, finally, lead to neurodegeneration. Here, we review the histopathological AD hallmarks and discuss the two-hit vascular hypothesis of AD, emphasizing the role of neurovascular dysfunction as an early factor that favors vascular A beta aggregation and neurodegeneration. Addtionally, we emphasize that pericyte degeneration is a key and early element in AD that can trigger amyloid vascular accumulation and NVU/BBB dysfunction. Further research is required to better understand the early pathophysiological mechanisms associated with NVU alteration and CAA to generate early biomarkers and timely treatments for AD.

Automated summary

Alzheimer's disease is characterized by progressive loss of cognitive functions and short-term memory, with neuropathological lesions including neuritic plaques and neurofibrillary tangles composed of beta-amyloid peptide and tau proteins. Vascular dysfunction and amyloid deposition around blood vessels may play a key role in the early pathophysiology of AD, leading to neuroinflammation, synaptic dysfunction, and ultimately neurodegeneration. Further research is needed to understand these mechanisms and develop early biomarkers and treatments.