Heart failure and Alzheimer's disease

Abstract

It has recently been proposed that heart failure is a risk factor for Alzheimer's disease. Decreased cerebral blood flow and neurohormonal activation due to heart failure may contribute to the dysfunction of the neurovascular unit and cause an energy crisis in neurons. This leads to the impaired clearance of amyloid beta and hyperphosphorylation of tau protein, resulting in the formation of amyloid beta plaques and neurofibrillary tangles. In this article, we will summarize the current understanding of the relationship between heart failure and Alzheimer's disease based on epidemiological studies, brain imaging research, pathological findings and the use of animal models. The importance of atherosclerosis, myocardial infarction, atrial fibrillation, blood pressure and valve disease as well as the effect of relevant medications will be discussed.

Keywords: Alzheimer′s disease; dementia; heart failure; neurocardiology; neurovascular unit.

Figure 1

The neurovascular unit, amyloid beta clearance and formation of amyloid beta plaques. The blood–brain barrier is composed of endothelial cells supported by a basement membrane and astrocytic feet. The blood–brain barrier represents an important part of a functional structure known as the neurovascular unit, which also includes pericytes and microglia. Amyloid beta is cleared by transcytosis through the cells of the blood–brain barrier and by phagocytosis by microglia. Disruption of the neurovascular unit is characterized by dysfunctional endothelial cells with abnormal intercellular connections, thickening and rupture of the basement membrane, swelling of astrocytic end feet and activated pericytes and microglial cells. The breakdown of the blood–brain barrier inhibits amyloid beta clearance via transcytosis. Activated microglia are not able to phagocytose its excess which results in accumulation of amyloid beta plaques.

Figure 2

Model of the relationship between heart failure and Alzheimer′s disease. This model shows the possible direct and indirect pathways of the contribution of heart failure to the development of Alzheimer′s disease. Low cardiac output may directly lead to reduced cerebral blood flow. Neurohormonal activation, inflammation and microvascular dysfunction may indirectly contribute to impaired perfusion and therefore insufficient oxygenation of the brain. Hypoxia induces hyperphosphorylation of tau protein and expression of beta secretase which cleaves amyloid precursor protein. In addition, insufficient blood supply causes disruption of cells comprising the neurovascular unit and induces oxidative stress.

Figure 3

Schematic diagram of the complex relationship between heart failure and Alzheimer′s disease.