Shared Molecular Mechanisms among Alzheimer's Disease, Neurovascular Unit Dysfunction and Vascular Risk Factors: A Narrative Review

Abstract

Alzheimer's disease (AD) is the most common type of dementia, affecting 24 million individuals. Clinical and epidemiological studies have found several links between vascular risk factors (VRF), neurovascular unit dysfunction (NVUd), blood-brain barrier breakdown (BBBb) and AD onset and progression in adulthood, suggesting a pathogenetic continuum between AD and vascular dementia. Shared pathways between AD, VRF, and NVUd/BBB have also been found at the molecular level, underlining the strength of this association. The present paper reviewed the literature describing commonly shared molecular pathways between adult-onset AD, VRF, and NVUd/BBBb. Current evidence suggests that VRF and NVUd/BBBb are involved in AD neurovascular and neurodegenerative pathology and share several molecular pathways. This is strongly supportive of the hypothesis that the presence of VRF can at least facilitate AD onset and progression through several mechanisms, including NVUd/BBBb. Moreover, vascular disease and several comorbidities may have a cumulative effect on VRF and worsen the clinical manifestations of AD. Early detection and correction of VRF and vascular disease by improving NVUd/BBBd could be a potential target to reduce the overall incidence and delay cognitive impairment in AD.

Keywords: Alzheimer’s disease; cigarette smoking; dyslipidemia; hypertension; type 2 diabetes mellitus; vascular risk factors.

Figure 1

Known interactions between vascular and neurodegenerative factors in AD.

Figure 2

Shared molecular mechanisms linking vascular risk factors, vascular pathology, APOE genotype, neurovascular unit dysfunction, blood-brain barrier dysfunction and Alzheimer’s disease onset and progression. Legend: AGE: advanced glycation end products; AT-II: angiotensin receptor 2; CypA: cyclophilin A; HyperC-VMSCs: hyper-contractile phenotype vascular muscular smoot cells; LRP-1: low-density lipoprotein receptor-related protein-1; nAChrs: nicotinic acetylcholine receptors subunit α7; IGF1: insulin growth factor; RAGE: advanced glycation end products receptor; sICAM1: soluble intercellular adhesion molecule-1; sVCAM1: soluble vascular cell adhesion molecule 1.