EFFECTS OF STRESS, ALLOSTATIC LOAD, AND THE EXPOSOME ON BRAIN STRUCTURE, FUNCTION, AND COGNITION IN THE EARLY-TO-MIDLIFE TRANSITION

ABSTRACT FOR PROJECT 1 - REVISED
"Stress" accelerates biological aging, increases risk for many diseases, including Alzheimer's disease (AD) and AD-related dementias (ADRD), and increases mortality. Allostasis is the process by which an organism responds to stress to regain homeostasis, engaging a host of physiological, biochemical, and molecular processes working in concert. When over-stressed, these responses produce unhealthy long-lasting changes in cell and organ structure and function, including the brain. "Allostatic load" has been a useful construct encompassing such wear and tear in the body and the brain, and animal and some human research have proposed many ways in which chronic stress directly or indirectly affects neurons, glia and neurochemistry, with associated changes in regional brain connectivity and function that would increase vulnerability to dementia in later life. To address when, how and by what mechanisms stress and allostatic load increase the brain's vulnerability to AD/ADRD in later life requires a lifespan perspective and a large, richly phenotyped longitudinal cohort. Project 1 will investigate how stress affects the brain's structure, function and neurochemistry across adulthood. Our overarching model is that higher levels of stress in younger and middle-aged adults leads to greater allostatic load and associated cardiovascular and metabolic health problems in middle age. Allostatic load and hypertension, obesity and insulin resistance alter the inflammatory, vascular and metabolic milieu of the brain, increasing vulnerability to AD/ADRD dementias of later life. Project 1 will focus on the young adult to mid-life transition, a stage of adult life when stress levels are highest and the earliest signals of brain vulnerability emerge. Mechanistically, we focus on immune dysregulation and inflammation as an important early feature of chronic stress states, allostatic load, and the emergence of amyloid, tau and neurodegeneration. AABC and Project 1 also expands its assessments to characterize the social determinants of health and the exposome in order to increase understanding of the increased vulnerability these groups have for AD/ADRD. In Aim 1, we determine the effects of stress measures on brain structure, function, neurochemistry and cognition, especially in AABC's younger adult to middle-aged participants. In Aim 2, we determine the effects of stress measures on innate immune dysregulation, allostatic load and neurodegeneration biomarkers and use mediation models to evaluate the relationships among stress, allostatic load, brain vulnerability and cognition. Aim 3 investigate the effects of status-related social determinants, stressors and stress experience on allostatic load, brain structure, function and neurochemistry and cognition in ethnoracial groups. In Aim 4, we will synergize with Projects, 2, 3 and 4 by investigating the effects of stress, innate immune dysregulation and allostatic load in relation to physical activity, sleep and resilient lifestyle factors of Project 2, menopause in Project 3, and the manifest cerebrovascular and AD/ADRD diseases in resilient/resistant vs. unsuccessful aging in Project 4.

Grant Number: 5U19AG073585-05
NIH Institute/Center: NIH
Principal Investigator: STEVEN ARNOLD