Friday, April 26, 2024
4/26/2024
Application Number: 1 K99 AG071742-01 PI: MA, YUAN Modified Project Summary/Abstract Section Epidemiologic, imaging and pathological studies of the role of blood pressure variability in the etiology of Alzheimer's disease and related dementias Project Summary The etiology of Alzheimer's disease and related dementias (ADRD; hereinafter, used interchangeably with dementia) in older adults is multifactorial, and vascular risk factors, especially hypertension, are major modifiable contributors. However, the relationship between blood pressure (BP) and dementia is far from clear. Increased BP variability over different periods has been linked to cardiovascular disease and mortality risk independent of static BP levels. Emerging evidence has also suggested BP variability as a novel risk factor for Alzheimer's disease and related dementias. But the clinical translation of BP variability for the risk stratification and prevention of Alzheimer's disease and related dementias has been hampered by the lack of standards for assessing BP variability and the lack of knowledge on the underlying mechanisms. The goals of this project are to 1) comprehensively quantify the epidemiological relationship between BP variability and Alzheimer's disease and related dementias and 2) identify the causal pathways linking BP variability to Alzheimer's disease and related dementias. To accomplish these, the data from 6 prospective cohort studies across the US and Europe will be analyzed: the Framingham Heart Study, the Rotterdam Study, the Three-City Study, the Atherosclerosis Risk in Communities Study, and the Rush Religious Orders Study and Memory and Aging Project. In Aim 1, the relationship between 3 types of BP variability (visit-to-visit variability, beat-to-beat variability, and postural variability) and the risk of Alzheimer's disease and related dementias will be quantified by pooling individual data (n~31,274) from the above 6 cohort studies using consistent approaches. Aims 2 and 3 will further investigate the mechanisms underlying these epidemiologic relationships. Specifically, in Aim 2, the extent to which cerebral small vessel disease mediates the relationship between BP variability and the risk of Alzheimer's disease and related dementias among participants with brain MRI data will be determined using causal mediation analysis. Aim 3 (R00 phase) extends the investigation to Alzheimer’s disease (AD) pathology using neuropathology and neuroimaging data, where the interplay between BP variability, vascular pathology, AD pathology and the risk of Alzheimer's disease and related dementias will be characterized. This K99 project will enhance the PI’s prior training in medicine and epidemiology and further expand her expertise in 1) causal inference methods, 2) employing neuroimaging and neuropathology data, and 3) incorporating clinical and mechanistic relevance in epidemiological studies. This project will enable the PI to establish herself as an independent researcher using advanced epidemiological methods and interdisciplinary skills to make significant contributions to the prevention of Alzheimer's disease and related dementias.
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