Impaired Aβ clearance: a potential link between atherosclerosis and Alzheimer’s disease

Abstract

Alzheimer’s Disease (AD) and atherosclerosis remain two of the largest public health burdens in the world today. Although traditionally considered distinct pathological entities, mounting epidemiologic, clinical and experimental evidence suggests that cerebrovascular atherosclerosis and AD interact reciprocally to disrupt brain structure and function. Whereas the hypoperfusion and hypoxia caused by atherosclerosis of cerebral vessels may enhance the production of amyloid-β peptide (Aβ), a peptide central to AD pathology, Aβ, in turn, may promote formation of atherosclerotic lesions through vascular oxidative stress and endothelial dysfunction leading to additional vascular damage. Here, we briefly review evidence suggesting that impaired clearance of Aβ is an additional, simultaneously occurring mechanism by which AD and cerebrovascular disease may be causally linked. We examine the literature supporting mechanisms by which flow-limiting large-artery stenosis, arterial stiffening and microvascular dysfunction could contribute to AD pathophysiology by impairing Aβ clearance and elevating brain levels of Aβ. Finally, we highlight the need for further research to improve our understanding of the complex interactions of AD and atherosclerosis with Aβ clearance, which may ultimately serve to guide the development of novel diagnostic and therapeutic approaches for this devastating and highly prevalent condition.

Association Between Midlife Vascular Risk Factors and Estimated Brain Amyloid Deposition

“…An alternative hypothesis, supported by the findings of this study, is that vascular disease, particularly at the arteriolar level, might reduce vascular clearance of amyloid. 35,36 …”

Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease

“…Atherosclerosis has been implicated in the pathogenesis of dementia and AD, and it has several overlapping risk factors including diabetes, hypercholesterolemia and aging [128]. Recently, a large cohort autopsy found that 77% of 410 AD subjects had grossly apparent circle of Willis atherosclerosis, which occurred more often than in non-AD subjects [129].…”

4D flow MRI for intracranial hemodynamics assessment in Alzheimer’s disease

“…This failure to dispose of soluble metabolites from the brain may have important implications for the pathogenesis of dementia. [5][6][7][8] Consequently, there is interest in noninvasive methods to assess cerebrovascular hemodynamics as potential systemic indicators of AD. 9 One common approach for the probing of intracranial hemodynamic parameters is the use of Transcranial Doppler ultrasound (TCD), which has been used successfully in other hemodynamic studies.…”