Cognitive Impairment and Dementia, Vascular Brain Injury, and Atrial Myopathy: Implications for Prevention of Alzheimer's Disease-Related Dementias

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Alzheimer’s Disease (AD) and AD-Related Dementias (ADRD) are projected to affect 115 million people worldwide by 2050. Vascular contributions to cognitive impairment and dementia (VCID)—a primary type of ADRD—is a major research focus for the NIH, which has called for the need to discover novel non-invasive, non-CNS organ-related (e.g., heart) markers to detect presence and progression of VCID (ADRD summit 2022). The oldest-old (>85 years) are the fastest growing segment of the population in most of the world and have the highest rates of dementia. Yet, the risk factors for AD/ADRD in the oldest-old are poorly understood and are different from the young-old (65-74 years) and middle-old (75-84 years). For example, in the oldest- old, hypertension is protective and about half of all dementia cases is related to non-AD pathologies such as microbleeds and small vessel ischemic disease. Atrial myopathy (defined by altered left atrial [LA] function or structure) is an underrecognized but important contributor to VCID, and is associated with lower cognitive function, greater vascular brain injury, and incident dementia. Atrial myopathy is also associated with greater global cortical β-amyloid (AD pathology). However, the extent to which atrial myopathy is associated with dementia risk in the oldest-old is unknown. Furthermore, prior research has evaluated atrial myopathy as a static entity and the etiology and prognostic relevance of atrial myopathy progression are not known. These are crucial barriers to targeting this potentially modifiable risk factor for AD/ADRD prevention. Thus, the overarching objectives of this project are to determine the prognostic importance of atrial myopathy for incident dementia in the oldest-old; relate atrial myopathy progression or trajectories of atrial myopathy in the young-old and middle-old to incident dementia and change in neuroimaging and plasma biomarkers of AD/ADRD; and define the clinical/lifestyle risk factors and proteomic and metabolomic signatures of adverse atrial myopathy trajectories. We will leverage the extensively well-characterized Atherosclerosis Risk in Communities (ARIC) cohort (including the longest followed cohort of Black adults) with existing MCI/dementia ascertainment and neuroimaging data, and will perform serial measurement of LA function, measure circulating AD/ADRD biomarkers, and conduct ambulatory heart rhythm monitoring to rigorously detect atrial fibrillation (AF) so that we can account for the contribution of AF to associations. To ensure rigor and reproducibility, we will replicate findings in 2 independent community-based cohorts: Multiethnic Study of Atherosclerosis and the Jackson Heart Study. This project will have significant impact. Our findings will (a) broaden VCID to encompass atrial myopathy as an insult to the neurovascular unit, thus identifying a new avenue for AD/ADRD treatment or prevention; (b) clarify the pathology underlying the neurocognitive impact of atrial myopathy, hence facilitating research to discover novel AD/ADRD prevention strategies; (c) identify specific lifestyle or molecular targets for atrial myopathy progression, thus informing future clinical trials aimed at preventing AD/ADRD.