PROJECT SUMMARY. Alzheimer’s disease and related dementias (ADRD) has become a major public health crisis. To date, therapeutic strategies for Alzheimer’s disease have been largely ineffective resulting in an increased focus on identifying effective prevention strategies. Daily 24-hour activity behaviors (sleep, physical activity, and sedentary time) may be modifiable risk factors for ADRD. A better understanding of these risk factors may provide an opportunity for early prevention, particularly in the asymptomatic phase prior to the development of ADRD-related pathology. The availability of longitudinal actigraphy data to objectively-measure 24-hour activity in a strongly ADRD-phenotyped cohort has created the ideal opportunity to investigate potential pathways linking 24-hour activity behaviors with ADRD. The objective of this K01 is to longitudinally investigate changes in 24-hour activity with changes in cognition, structural neuroimaging, and fluid biomarkers of Alzheimer’s disease and concomitant pathological pathways prior to the onset of clinical dementia. I will leverage data from the Vanderbilt Memory and Aging Project (VMAP) cohort with repeated measures of actigraphy, brain MRI, and fluid biomarkers of Alzheimer’s disease neuropathology and concomitant injury. The central hypothesis of this proposal is changes in 24-hour activity will be associated with cognitive decline, structural neuroimaging changes, and Alzheimer’s disease and concomitant pathway changes, preceding symptom onset. Based on this hypothesis, the proposal aims to 1) characterize associations between changes in 24-hour activity and cognitive decline, 2) examine changes in 24-hour activity in relation to MRI markers of neurodegeneration and small vessel disease, and 3) evaluate changes in 24-hour activity behaviors with fluid biomarkers of Alzheimer’s disease neuropathology and concomitant pathways. Taken together, these aims will combine objective measurement of 24-hour activity with cognitive, neuroimaging, and state of the art fluid biomarker data to fill existing gaps in the research. Simultaneously, throughout the award, the candidate will gain advanced training in 1) Alzheimer’s disease pathophysiology and epidemiology; 2) measurement and modeling of structural imaging and fluid biomarkers of Alzheimer’s neuropathology and concomitant pathways of injury; and 3) advanced statistical methods, positioning the candidate to become a leader in the fields of aging and Alzheimer’s disease epidemiology. Vanderbilt University Medical Center and the Vanderbilt Memory and Alzheimer’s Center provide the ideal environment to complete the proposed research and training activities. The overall goal of this K01 is to inform a series of R01 awards and independent research program focused on identifying and characterizing behavioral risk factors for ADRD. With the support of this K01 award and expert mentorship, the candidate will achieve this goal and successfully transition to in...