Vascular hypothesis of Alzheimer’s disease: role of apoE and apoE receptors

Abstract

Background Alzheimer’s disease (AD) is a progressive neurodegenerative disease that has emerged as the most prevalent form of late-life dementia in humans [1]. Production of amyloid-b (Ab) from the amyloid precursor protein (APP) and its subsequent accumulation, aggregation and deposition in the brain are central events in the pathogenesis of AD [1]. Cerebral amyloid angiopathy (CAA) is a major pathological feature of AD where amyloid spreads and deposits throughout the blood vessel walls in the central nervous system. These pathogenic events induce a specific clinical presentation profile including cerebral hemorrhage, stroke, ischemic infarctions, subarachnoid hemorrhage, seizures, cognitive impairment and dementia [2]. While Ab is a key molecule in AD, epidemiological studies have shown that several well-established risk factors for AD, including diabetes mellitus, atherosclerosis, stroke, hypertension, transient ischemic attacks, microvessel pathology and smoking, have a vascular component that reduces cerebral perfusion [3]. In fact, detection of regional cerebral hypoperfusion through neuroimaging techniques can preclinically identify individuals at risk for AD. Further, cerebral hypoperfusion precedes hypometabolism, cognitive decline, and neurodegeneration in AD [3]. Therefore, disturbance of cerebrovascular system is likely a major contributor to AD pathogenesis. Among the three human apolipoprotein E (apoE) isoforms (E2, E3 and E4), APOE4 is the strongest genetic risk factor for late-onset AD. The most consistent finding that differentiates apoE4 from apoE3 is their respective roles in brain Ab clearance, where apoE4 is less efficient than apoE3 in promoting Ab clearance [4]. In addition, APOE4 also increases the risk for CAA and vascular dementia [4]. Because apoE4 is known to damage blood-brain barrier (BBB) integrity and reduces small cerebral vessels [5], apoE is likely involved in the maintenance of cognitive function through regulating the function of cerebrovascular systems.