The Role of Vascular Factors in Late-Onset Sporadic Alzheimers Disease. Genetic and Molecular Aspects

Abstract

Alzheimer's disease (AD) is a late-onset progressive neurodegenerative disorder which results in the irreversible loss of cortical neurons, particularly in the associative neocortex and hippocampus. AD is the most common form of dementia in the elderly. Apart from the neuronal loss, the pathological hallmarks are extracellular senile plaques, containing the peptide beta-amyloid (Abeta), and neurofibrillary tangles. The Abeta cascade hypothesis remains the main pathogenetic model, as suggested by familiar AD, mainly associated to mutation in amyloid precursor protein and presenilin genes. The remaining 95% of AD patients are mostly sporadic late-onset cases, with a complex aetiology due to interactions between environmental conditions and genetic features of the individual. A relationship between genetic and acquired vascular factors and AD has been hypothesized. Many vascular risk factors for AD, such as atherosclerosis, stroke and cardiac disease in the aging individual, could result in cerebrovascular dysfunction and trigger AD pathology. A major vascular susceptibility factor gene is the apolipoprotein E gene, found to be associated with sporadic late-onset AD cases. Another interesting vascular susceptibility gene is angiotensin converting enzyme. Other possible genes include VLDL-R, LRP, NOS3, CST3, OLR1, MTHFR, PON1 and VEGF, but many of the related studies have shown conflicting results. In this paper, we review the role of molecular vascular abnormalities and of the "vascular risk" genes supposed to be involved in the pathogenesis of AD, in an attempt to provide a comprehensive picture of what is known about the mechanisms underlying the role of vascular factors in late-onset sporadic AD.

Amyloid-β Production: Major Link Between Oxidative Stress and BACE1

“…It is well known that patients with stroke and cerebral infarction are at risk of AD (Rocchi et al 2009).…”

The link between cardiovascular risk, Alzheimer's disease, and mild cognitive impairment: support from recent functional neuroimaging studies

“…88 Based on the above epidemiological, clinical, and structural neuroimaging findings, it has been proposed recently that AD and VaD actually represent two extremes of a dementia spectrum ranging from patients with pure VaD to patients with pure AD, with a majority of patients having contributions from both neuropathological pathways. 53,74,89,90 Figure 1 (adapted from Viswanathan et al 90 ) illustrates the concept of a spectrum ranging from pure AD to pure VaD. Such lines of evidence have also provided support to a more ambitious ''vascular hypothesis'' for AD, which proposes that the neuropathological changes that characterize AD would originate primarily from microvascular abnormalities.…”

Stroke and Dementia in Atrial Fibrillation

“…Today, it is believed to be associated with excessive extracellular beta-amyloid and intracellular hyperphosphorylated tau protein accumulation eventually leading to the loss of cholinergic neurons and relative glutamate excess. (Rocchi et al, 2009) VAD, accounting for 10-20% of all dementia patients, is characterized by a stepwise deteriorating course and a patchy distribution of neurologic deficits (affecting some functions and not others) caused by cerebrovascular disease. It is not a single disease, but rather a group of syndromes relating to different vascular mechanisms.…”

“…Other possible genes include VLDL-R, LRP, NOS3, CST3, OLR1, MTHFR, PON1 and VEGF, but many of the related studies have shown conflicting results. (Rocchi et al, 2009) Some strokes are clinically detected, while others go undetected. Silent strokes are, also, associated with higher age, elevated blood pressure and AF.…”