Genetic Predisposition to Elevated Blood Pressure and Midlife Cognitive Function: Exploring the Impact of Lifespan Risk Factors and Polygenic Risk Scores

Tulane University Of Louisiana, New Orleans LA

Investigators

Abstract

Hypertension (HTN) is the most common preventable and treatable condition that increases the risk for dementia. However, RCTs for blood pressure (BP) control have shown that the benefits are highly variable from person to person, and others have reported null findings. Polygenic Risk Scores of elevated BP (BP PRS) have identified individuals with increased risk for hypertension (HTN), even prior to manifesting elevated BP. Despite the disproportionate burden of elevated BP and dementia outcomes in minoritized groups, few BP PRS are available for individuals of non-European ancestry. This K08 aims to investigate the relationship between genetic predisposition to HTN with midlife cognitive function and Alzheimer’s Disease and Related Dementia (ADRD) in late life, as well as its potential predictive value when combined with life course modifiable risk factors information. The study seeks to test the hypothesis that genetic predisposition to elevated BP impacts midlife cognitive function and dementia later in life and has added predictive value when combined with early life course modifiable risk factors by pursuing three specific aims: Aim 1: Evaluate the association between a multi-ancestry BP PRS and midlife cognitive function by leveraging data from the Bogalusa Heart Study (BHS). The BHS is a unique longitudinal cohort with data from childhood on rural, low-income, Black and White, men and women entering their 6th decade of life. Aim 2: Examine the association between multi-ancestry BP PRS and midlife MRI-based brain markers of disease. This aim will investigate whether higher BP PRS levels are associated with more cerebral white matter lesions and brain volumes in midlife and if these associations are modified by life course modifiable risk factors and midlife subclinical cardiovascular indicators. Aim 3: Assess the utility of BP PRS in predicting midlife cognition and dementia syndromes in late life by leveraging data from well- characterized longitudinal cohorts, including CARDIA and the HRS. This aim will also determine to what extent BP PRS enhances the predictive value of life course ADRD risk factors. The long-term goal of the candidate, Dr. De Anda-Duran, is to become an independent investigator focusing on vascular influences on brain health across the lifespan. The proposed project will provide training and expertise in genetic epidemiology, health disparities, and neuroimaging methods. This includes advanced statistical techniques for analyzing genetic data, understanding health disparities and their impact on ADRD, and using neuroimaging to study brain structure and function. The integration of these skills will enable the identification of high-risk individuals who might benefit most from BP control pharmacological treatments and lifestyle interventions. Successful completion of this project will generate preliminary data for a future, large-scale multi-cohort R01 application. Findings from this project will aid in identifying when, in the lifespan, BP control and lifestyle modification interventions might be more beneficial and shed light on effective multidomain approaches to significantly reduce ADRD risk.