Vascular Risk Factors and Alzheimer’s Disease: Blood-Brain Barrier Disruption, Metabolic Syndromes, and Molecular Links

Article type: Review Article

Authors: He, Jin-Ting^a | Zhao, Xin^b | Xu, Lei^{a; *} | Mao, Cui-Ying^{c; *}

Affiliations: [a] Department of Neurology, China-Japan Union Hospital, Jilin University, Changchun, Jilin Province, China | [b] Department of Paediatrics, The First Hospital of Jilin University, Changchun, Jilin Province, China | [c] Department of Cardiology, China-Japan Union Hospital, Jilin University, Changchun, Jilin Province, China

Correspondence: [*] Correspondence to: Lei Xu, Department of Neurology, China-Japan Union Hospital, Jilin University, 126 Xiantai Street, Changchun 130033, Jilin Province, China. E-mail: xl1974@yahoo.com; Cui-Ying Mao, Department of Cardiology, China-Japan Union Hospital, Jilin University, 126 Xiantai Street, Changchun 130033, Jilin Province, China. E-mail: maocyyy@yahoo.com.

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder, marked by cortical and hippocampal deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles and cognitive impairment. Studies indicate a prominent link between cerebrovascular abnormalities and the onset and progression of AD, where blood-brain barrier (BBB) dysfunction and metabolic disorders play key risk factors. Pericyte degeneration, endothelial cell damage, astrocyte depolarization, diminished tight junction integrity, and basement membrane disarray trigger BBB damage. Subsequently, the altered expression of low-density lipoprotein receptor-related protein 1 and receptor for advanced glycation end products at the microvascular endothelial cells dysregulate Aβ transport across the BBB. White matter lesions and microhemorrhages, dyslipidemia, altered brain insulin signaling, and insulin resistance contribute to tau and Aβ pathogenesis, and oxidative stress, mitochondrial damage, inflammation, and hypoperfusion serve as mechanistic links between pathophysiological features of AD and ischemia. Deregulated calcium homeostasis, voltage gated calcium channel functioning, and protein kinase C signaling are also common mechanisms for both AD pathogenesis and cerebrovascular abnormalities. Additionally, APOE polymorphic alleles that characterize impaired cerebrovascular integrity function as primary genetic determinants of AD. Overall, the current review enlightens key vascular risk factors for AD and underscores pathophysiologic relationship between AD and vascular dysfunction.

Keywords: Alzheimer’s disease, amyloid-β , blood-brain barrier, inflammation, ischemia, metabolic syndrome, oxidative stress, p-tau

DOI: 10.3233/JAD-190764

Journal: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 39-58, 2020