ABSTRACT In its earliest stage Alzheimer’s disease does not manifest cognitive impairment while dementia is a late manifestation. A biomarker to identify preclinical Alzheimer’s dementia is crucial for treatments aimed at its prevention. Alzheimer’s disease can also degrade non-cognitive functions like mobility that precedes and predicts cognitive impairment in many older adults. To use mobility as a biomarker, it is crucial to identify the metrics that best predict Alzheimer’s dementia and the mechanisms that account for this association. We must think to move. Mobility requires motor and cognitive abilities that derive from distinct brain regions. This may explain why mobility is an early predictor of dementia. Yet, motor testing usually only quantifies movement duration. So, the role of cognitive abilities in the association of mobility with Alzheimer’s dementia is unclear. Unobtrusive sensors can be used to assess cognitive and motor metrics crucial for mobility. This study will use novel digital mobility phenotyping to improve the prediction of Alzheimer’s disease dementia and identify brain pathologies and proteins that inform on this association. This study responds to NOT-AG-20-053 and will add new resources to those available from 1000 older adults in the Rush Memory and Aging Project (R01AG17917). To improve the prediction of Alzheimer’s dementia, we will add cognitive mobility metrics e.g., motor planning and attentional metrics to a single-testing session. To capture the varied cognitive demands during everyday mobility, we will also add new multi-day mobility metrics obtained from a wrist sensor. Motor planning is related to supplementary motor area (SMA) and task attention and executive function are regulated by dorsolateral prefrontal cortex (DLPFC). So, we focus on these regions to identify mechanisms shared by mobility and Alzheimer’s disease dementia. In 200 decedents with available brain pathologies, we will collect new proteome data from SMA to complement the available DLPFC proteome. Aim 1 will add new digital cognitive mobility metrics to motor metrics obtained from a single-testing session as well as novel multi-day mobility metrics to improve the prediction of Alzheimer’s dementia. Sensors yield large numbers of mobility metrics. Aim 1 will isolate individual metrics that predict Alzheimer’s dementia. Aim 2 will analyze these novel metrics with a second approach to identify different mobility subgroups that may have varied risks of Alzheimer’s dementia. To inform on the mechanisms underlying the association of mobility and Alzheimer’s dementia, Aim 3 will use brain pathologies to determine the pathologic bases for these mobility subgroups. Aim 4 will collect proteome from SMA and DLPFC to identify cortical proteins independently related to mobility subgroups when controlling for ADRD pathologies. From the set of proteins related to mobility, we will identify a subset that are also related to Alzheimer’s dementia. This stud...