The cerebromicrovasculature: a key player in the pathogenesis of Alzheimer's disease

Neuronal cell death is the primary underlying pathogenic lesion in Alzheimer's disease (AD). Despite intense research efforts, the mechanisms that contribute to neuronal cell death have not been clarified. In this debate we address the question, Is AD a vascular or metabolic disorder? Here we defend the hypothesis that the cerebromicrovasculature is a key player in the pathogenesis of AD. Evidence is presented that vascular amyloid beta (Abeta) is more closely associated with tau pathology than the distribution of diffuse or neuritic plaque Abeta. Furthermore, brain endothelial cells are identified as important regulators of the neuronal microenvironment, including Abeta levels. Finally, evidence is presented that brain endothelial cells undergo cellular and biochemical changes in AD and that the release of neurotoxic factors from these dysfunctional cells contributes to the neuronal cell loss characteristic of AD.