ABSTRACT FOR PROJECT 2 An effective disease-modifying treatment for Alzheimer’s dementia (AD) or AD related dementias (ADRD) is not available, underscoring the pressing need to identify brain health protective factors that reduce risk for cognitive decline, AD, and ADRD. A critical time that influences the impact of modifiable risk factors is the transition from midlife to late life (50 to 80 years). Research also has demonstrated the role of inflammation in neurodegeneration, and disrupting brain inflammation may reduce dementia risk. It is thus critical to determine relative contributions of these vulnerability/resiliency factors to cognitive health and inflection points when specific risk reduction interventions may be most effective. Findings from the Human Connectome Project (HCP) indicate a strong positive-negative mode of population covariation that links brain connectivity, demographics and behavior. This project offers an unprecedented opportunity to examine such factors longitudinally during a critical inflection point when lifestyle factors begin to initiate a downward brain health trajectory. To elucidate these relationships, this project will address the following specific aims focused on the mid to-late-life transition: (1) Determine the effects of modifiable vulnerability and resilience factors in the mid-to late-life transition (exercise, sleep, diet, stress (with P1); measures of health (Body Mass Index (BMI), blood pressure (BP), insulin resistance (HbA1c), cholesterol), on structural connectivity (measured with Diffusion Tensor Imaging (DTI); functional connectivity(resting state functional connectivity (rsFC); task fMRI) and cognition (2) Determine the unique contributions of AD risk factors and markers vs. modifiable lifestyle factors and health markers on the trajectory of brain and cognitive change across the mid-late life transition using cross-sectional and longitudinal analysis; (3) Identify the most likely structural model that connects brain and cognitive outcomes in the AABC longitudinal data with AD biomarkers, baseline cognitive, age, AD risk and lifestyle. 4) Integration with other projects and the Center as a whole to examine lifetime, non-linear trajectories of brain and cognitive aging, resistance to AD, risk, and resilience. To accomplish these aims, we will perform longitudinal follow-up of 764 subjects in the mid- to late-life transition (ages 50 to 80) and include measures assessing lifestyle and resilience (e.g., actigraphy, sleep, diet) and coordinate with the cores and other projects to include other measures and variables relevant to these aims. With the accumulation of evidence that mitigation of AD risk can delay or prevent the disease, there is a need to identify, inform and intervene in people at greatest dementia risk. When started early, even relatively modest risk reduction may translate to significant declines in disease incidence. This project offers the opportunity to leverage a well-studied cohort of normal aging middle-aged and older adults, many with a decade of longitudinal data.

NARRATIVE FOR PROJECT 2 Increases in life expectancy have led to a growing number of people at risk for age-related cognitive decline, and compelling scientific evidence points to the importance of lifestyle habits contributing to both vulnerability and resiliency to cognitive decline during the mid- to late-life transition. This project offers an unprecedented opportunity to examine these factors longitudinally during a critical inflection point when lifestyle factors begin to initiate a downward brain health trajectory- the mid-to late life transition.