Lifecourse Predictors and Mechanisms of Early Clinical ADRD among Black and White Adults in their Sixties

University Of California, San Francisco, San Francisco CA

Investigators

Abstract

ABSTRACT The physiologic and neuropathologic processes in Alzheimer disease (AD) and Alzheimer disease related disorders (ADRD) are insidious and take decades to develop. Furthermore, the likelihood of developing AD/ADRD is influenced by the interplay of genetics and risk/resilience factors, especially cardiovascular disease (CVD) risk factors and social determinants of health (SDOH), that operate over the life course. Given that the new AD disease modifying therapies are believed to be most effective in the early stages, as well as the tremendous burden that AD/ADRD places on patients, caregivers, and society, it is imperative to identify the earliest manifestations of these diseases in order to offer better prevention/treatment, particularly in more diverse populations. The transition from midlife to early late-life offers an exciting and under investigated time period for early clinical AD/ADRD development and how this may differ according to race and sex. We propose to conduct a Year 40 (when participants have a mean age of 65) cognitive assessment and AD/ADRD adjudication among the ongoing Coronary Artery Risk Development in Young Adults (CARDIA) study in order to investigate this early late-life transition to clinical AD/ADRD and to determine underlying mechanistic pathways that may highlight prevention opportunities. CARDIA is uniquely positioned to address this line of investigation as it has repeated cognitive and brain MRI measures over the midlife period and is comprised of roughly equal numbers of Black and White participants who have been followed since their 20’s. We hypothesize that the early late-life period (when participants are in their 60s) is a critical window of opportunity to identify the transition to early clinical AD/ADRD and determine how this is influenced by early neurodegenerative (assessed by MRI, genetics, blood AD biomarkers and other factors) as well as vascular pathways (assessed by CVD, genetics, MRI and other factors). In turn, because CARDIA is balanced by race and sex, we will be in an excellent position to investigate disparities in the midlife to late-life transition to early AD/ADRD and whether mechanistic drivers differ by sex and race. We will also identify the life course predictors of this early AD/ADRD with a particular focus on comprehensive measures of SDOH and determine how SDOH also may influence proposed mechanistic pathways and their changes over time. Finally, as part of an exploratory aim, we will develop a prognostic model for AD/ADRD in the 60s incorporating life course risk factors, MRI measures, AD biomarkers, genetics and other data elements. This model will be essential for future risk prognostication as AD/ADRD drug development and prevention strategies advance and there is need to identify people as early as midlife in order to target primary prevention. Findings from this innovative study will provide highly relevant results to the field of AD/ADRD by providing critical information on the midlife to early late-life transition to AD/ADRD, the mechanistic pathways behind these changes, SDOH influences, and the underpinnings of health disparities for AD/ADRD.