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Vascular contributions to Alzheimer's disease

Published:December 15, 2022DOI:https://doi.org/10.1016/j.trsl.2022.12.003

      Abstract

      Alzheimer's disease (AD) is the most common cause of dementia and is characterized by progressive neurodegeneration and cognitive decline. Understanding the pathophysiology underlying AD is paramount for the management of individuals at risk of and suffering from AD. The vascular hypothesis stipulates a relationship between cardiovascular disease and AD-related changes although the nature of this relationship remains unknown. In this review, we discuss several potential pathological pathways of vascular involvement in AD that have been described including dysregulation of neurovascular coupling, disruption of the blood brain barrier, and reduced clearance of metabolite waste such as beta-amyloid, a toxic peptide considered the hallmark of AD. We will also discuss the two-hit hypothesis which proposes a 2-step positive feedback loop in which microvascular insults precede the accumulation of Aß and are thought to be at the origin of the disease development. At neuroimaging, signs of vascular dysfunction such as chronic cerebral hypoperfusion have been demonstrated, appearing early in AD, even before cognitive decline and alteration of traditional biomarkers. Cerebral small vessel disease such as cerebral amyloid angiopathy, characterized by the aggregation of Aß in the vessel wall, is highly prevalent in vascular dementia and AD patients. Current data is unclear whether cardiovascular disease causes, precipitates, amplifies, precedes, or simply coincides with AD. Targeted imaging tools to quantitatively evaluate the intracranial vasculature and longitudinal studies in individuals at risk for or in the early stages of the AD continuum could be critical in disentangling this complex relationship between vascular disease and AD.

      Abbreviations:

      (beta-amyloid), AD (Alzheimer's disease), APP (amyloid precursor protein), AQP4 (aquaporin-4), ASL (arterial spin labeling), BBB (blood brain barrier), CAA (cerebral amyloid angiopathy), CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), CBF (cerebral blood flow), CCH (chronic cerebral hypoperfusion), cfPWV (carotid-to-femoral pulse wave velocity), CSF (cerebrospinal fluid), CSVD (cerebral small vessel disease), CVD (cerebrovascular disease), CVR (cerebrovascular reactivity), CVRF (cardiovascular risk factors), DCE (dynamic contrast enhanced), GLUT1 (glucose transporter 1), ICA (internal carotid artery), MCA (middle cerebral artery), MCI (mild cognitive impairment), MRI (magnetic resonance imaging), NFT (neurofibrillary tangles), NO (nitric oxide), NVU (neurovascular unit), PET (positron emission tomography), PSEN (presenilin), PWV (pulse wave velocity), RAGE (receptor for advanced glycation end products), VCID (vascular cognitive impairment and dementia), VHAD (vascular hypothesis for Alzheimer's disease), vSMC (vascular smooth muscular cells), WMH (white matter hyperintensity)
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