Cerebrovascular risk factors in Alzheimer's disease: Brain hemodynamics and pharmacogenomic implications

Abstract

Recent evidence indicates that different vascular risk factors are present in Alzheimer's disease (AD) and other prevalent dementia types probably contributing to deterioration of cerebrovascular function, thus enhancing neurodegeneration and premature neuronal death due to a reduction in brain perfusion. Brain blood flow shows a reduced velocity and increased pulsatility (PI) and resistance indices (RI) in different types of dementia and in diabetes and hypertension, as well. High levels of diastolic blood pressure correlate with diminished brain blood flow and elevated PI and RI, accompanied by cognitive deterioration. Nitric oxide (NO) levels are found increased in the sera and brain tissue of AD patients. Vascular risk factors (hyperglycemia, LDL-cholesterol, triglycerides, hypertension) and altered brain hemodynamic parameters correlate with APOE genotypes of which APOE-4/4 carriers represent the AD population with the highest cerebrovascular risk. In addition, the genomic profiles of patients with dementia integrating AD-related genes (APOE, PS1, PS2, cFOS) in a mini-tetragenic haplotype significantly differ from controls with an absolute genetic variation of about 50%-60%. Cerebrovascular dysfunction is a factor common to most types of dementia; however, genetic variation among different dementia types might be determinant for the activation of early vascular events inducing or accelerating neurodegeneration. In this regard, cerebrovascular dysfunction should be considered a potential therapeutic target in dementia.

Plasma Aβ42 correlates positively with increased body fat in healthy individuals

“…These risk factors appear to be exacerbated in individuals carrying the apolipoprotein E4 (APOE ε4) allele such that they have an increased risk of developing type -2 diabetes, hypertension, hypercholesterolaemia, cardiovascular disease and Alzheimer's disease (reviewed in [6,42]). This increase risk in APOE ε4 carriers maybe partly attributed to diet.…”

Alzheimer’s Disease—A Dysfunction in Cholesterol and Lipid Metabolism

“…Peripheral sources of Aβ peptides, cholesterol and inflammatory lipids, by transversing a damaged or leaky blood brain barrier, may further contribute to Aβ deposition in the AD brain (Aliev et al, 2003;Chaney et al, 2003). Due to a reduction in brain perfusion and altered hemodynamic properties, damaged, diseased, or dysfunctional cerebral vasculature may promote premature neuronal death as observed in multiple infarct dementia, in cerebral vascular dementia and in AD brain (Cacabelos et al, 2003;Aliev et al, 2003;Ravona-Springer et al, 2003;Fitzpatrick et al, 2004).…”

Alzheimer’s Disease and Diabetes

“…It has been suggested that differences in the clinical observations in AD and VaD patients may be due to the type, severity and location of vascular damage [133][134][135]. Furthermore, perturbations in vascular hemodynamics have been observed in VaD and AD [136,137], however, AD patients had comparatively less impairment in cerebral perfusion than those with VaD [138] suggesting that hemodynamic disturbances may underlie different types of dementia [138]. While the precise mechanism that vascular risk factors initiate cognitive decline remains elusive [139], T2DM have been identified as an important contributing factor to the development of VaD.…”