Examine the impact of congenital heart diseases on Alzheimer's disease.

Congenital heart diseases (CHDs) were revealed as a novel risk factor for Alzheimer's disease (AD) from a large-scale nationwide epidemiological study published in 2018. The primary goal of this research is to test the feasibility of using mouse models to examine the effect of CHDs on the onset and progression of AD. CHDs are the leading structural birth defects, affecting 1-5% of newborns. In contrast to the general misconception that CHDs mainly involve newborns/children, adult CHD patients now outnumber pediatric CHD patients by a ratio of 2:1. The prevalence of adults with CHDs is ~1% in the US. A growing number of adult CHD patients are aging. Understanding how CHDs impact AD is essential for the development of tailored clinical applications for adult CHD patients. The long interval between the occurrence of CHDs and the onset of AD makes it highly challenging to study how CHDs impact AD. Thus, it is not entirely surprising that few, if any, such studies have been published in the literature. We propose to test the feasibility of using mouse models to examine the CHD-AD interaction. Our unpublished study revealed that embryonic heart deletion of Chd7 led to inborn cardiomyopathy, and mutant mice could survive to 1-year old. We will crossbreed Chd7 heart-knockout mice with an AD model line to test our central hypothesis that congenital cardiomyopathy caused by embryonic heart deletion of Chd7 accelerates the onset and exacerbates the severity of AD-related deficits. Two aims are proposed. In Aim 1, we will test the effect of embryonic heart deletion of Chd7 on AD-related cognitive impairment. In Aim 2, we will determine the effect of embryonic heart deletion of Chd7 on AD-related neuropathology. This project is highly innovative by nature. Examination of how CHDs impact AD represents a completely new field for both AD and cardiovascular research. This project will test for the first time the feasibility of using mouse models to address the CHD-AD interaction and will set the foundation for future in vivo studies in this unexplored area. (AHA Program: Innovative Project Award)