Cardiovascular risk factors promote brain hypoperfusion leading to cognitive decline and dementia

Abstract

Heart disease is the major leading cause of death and disability in the world. Mainly affecting the elderly population, heart disease and its main outcome, cardiovascular disease, have become an important risk factor in the development of cognitive decline and Alzheimer's disease (AD). This paper examines the evidence linking chronic brain hypoperfusion induced by a variety of cardiovascular deficits in the development of cognitive impairment preceding AD. The evidence indicates a strong association between AD and cardiovascular risk factors, including ApoE(4), atrial fibrillation, thrombotic events, hypertension, hypotension, heart failure, high serum markers of inflammation, coronary artery disease, low cardiac index, and valvular pathology. In elderly people whose cerebral perfusion is already diminished by their advanced age, additional reduction of cerebral blood flow stemming from abnormalities in the heart-brain vascular loop ostensibly increases the probability of developing AD. Evidence also suggests that a neuronal energy crisis brought on by relentless brain hypoperfusion may be responsible for protein synthesis abnormalities that later result in the classic neurodegenerative lesions involving the formation of amyloid-beta plaques and neurofibrillary tangles. Insight into how cardiovascular risk factors can induce progressive cognitive impairment offers an enhanced understanding of the multifactorial pathophysiology characterizing AD and ways at preventing or managing the cardiovascular precursors of this dementia.

Figure 1

Cardiovascular risk factors reported to promote progressive cognitive decline leading to dementia in the elderly population. Reduced cardiac output (<3.4 ± 0.5 L/min) in the absence of clinically identified stroke can promote hypotension, heart failure, hypoxia, and increased (↑) vascular resistance associated with cognitive decline [39, 42, 63, 64] and ostensibly, Alzheimer's disease [173]. Aortic and mitral valve regurgitation (regurg) and/or valvular thickening can impair normal cardiac output. Aortic stiffening is associated with aging, hypertension, and atherosclerosis and is believed to result in brain microvascular damage, leading to cerebral hypoperfusion and cognitive decline [35, 118]. Left ventricular wall motion abnormalities mainly result from myocardial ischemia. Atrial fibrillation is a risk factor for cardioembolic events, especially stroke and for Alzheimer's disease [71]; it is the most common arrhythmia in the elderly population. Epidemiologic and clinical evidence indicates that coronary artery disease, the leading cause of mortality in the United States, is a potential risk factor for Alzheimer's disease [78, 109]. Left ventricular hypertrophy may be asymptomatic, mild, moderate, or severe and is a reported risk factor to cognitive decline in middle age but loses its predictive value in advanced age [174]. Presence of the ApoE₄ allele, a genetic risk factor to Alzheimer's dementia, increases the risk of coronary heart disease by about 40% [114]. Presence of two or more cardiovascular risk factors may significantly accelerate the onset of cognitive deficits [161].

Figure 2

Hypothetical model based on the collective evidence available showing how cardiovascular risk factors give rise to disturbed hemodynamic flow patterns inducing cerebral hypoperfusion. Chronic insufficiency of blood flow to the brain may reach a critically attained threshold of cerebral hypoperfusion (CATCH) [19] responsible for lowered energy substrate delivery and creation of a neurono-glial energy crisis, initially in brain regions where memory and learning are localized. Further downstream, an increase in protein pathology (↑ proteinopathy), featuring protein misfolding of Abeta peptide, ensues followed by impaired clearance of waste products including Abeta [175]. Reduced Abeta clearance from the brain is possibly due, as we predicted, to an impaired microcirculation causing an ineffective efflux of waste products [121]. Deficits (↓) of nonmemory executive function, verbal and mental abilities, and psychomotor speed are ostensibly the first subclinical changes in cognitive dysfunction prior to more advanced cognitive impairment.