Converging pathogenic mechanisms in vascular and neurodegenerative dementia.

Abstract

Dementia is a common neurological syndrome with a major impact on the health and quality of life of the elderly. Although the causes of dementia are numerous, Alzheimer dementia (AD) and vascular dementia (VaD) are responsible for most cases.1 Recent basic and clinical investigations have provided evidence that AD and VaD, traditionally considered distinct clinical and pathophysiological entities, may share common features. In this brief review, we will present these advances and a synthesis, focusing on the impact that this new information may have on the diagnosis and treatment of these conditions. The neuropathology of AD is characterized by β-amyloid deposition in brain parenchyma and blood vessels and by neurofibrillary tangles.2 The Aβ peptide derives from a larger protein, the amyloid precursor protein (APP), that is cleaved by the proteases α and β secretases to produce Aβ1-40 and Aβ1-42.2 In familial forms of AD, mutations in the APP or presenilin genes promote amyloidogenic APP cleavage, leading to increased Aβ production.2 Present models of AD advocate that Aβ accumulation in the tissue produces the neuronal dysfunction and death that underlies the dementia.3 However, the mechanisms by which Aβ produces neuronal dysfunction have not been elucidated in full. Although Aβ is well-known to be cytotoxic,4–6 recent findings in transgenic mice overexpressing APP have demonstrated that Aβ also has profound effects on cerebrovascular regulation. Resting cerebral blood flow (CBF) is reduced in regions of the cerebral cortex and in the hippocampus of APP mice.7 The cerebral vessels of these mice do not respond to vasodilating agents, such as acetylcholine, that act by releasing endothelium-dependent relaxing factors.8 APP mice are unable to keep CBF constant during moderate hypotension or hypertension, indicating a disturbance in cerebrovascular autoregulation.9 Furthermore, the increase in …