PROJECT SUMMARY/ABSTRACT Our long-term goal is to accurately identify who is at risk of driving decline, to establish whether driving behavior can be used as a functional, neurobehavioral biomarker of Alzheimer disease (AD), to forecast when driving decline will occur, to intervene before the time of decline, and to prevent a significant number of crashes, injuries, and death. Our findings indicate that the long preclinical stage of AD, as reflected in amyloid and tau imaging and cerebrospinal fluid (CSF) biomarkers among cognitively normal older adults, is associated with poorer driving performance on a road test, as well as with fewer trips made in a personal vehicle. This project will test the extent to which an in-vehicle datalogger, measuring everyday driving behavior continuously, reflects underlying neuropathological AD and is associated with prevalent and incident cognitive impairment. This research is significant because 36 million licensed drivers are aged 65 years or older, and the number of older adults in the United States is expected to double by 2050, when 1 in 4 drivers will be 65+. Our work suggests that changes in driving, an instrumental activity of daily living that involves both cognitive and functional abilities, may reflect neuropathological AD and precede the emergence of dementia symptoms. Our Specific Aims will (1) Use established cerebrospinal fluid (CSF) and imaging biomarkers to define preclinical AD and test the ability of the Driving Real-world In-Vehicle Evaluation System (DRIVES) to distinguish persons with and without preclinical AD among cognitively normal individuals, and assess the ability of this system to predict the future onset of dementia, (2) Test the ability of the DRIVES data to distinguish cognitively normal persons from those with dementia cross-sectionally, and to examine driving behavior over time for both groups, (3) Determine whether the DRIVES data, combined with cognitive, health, and functional data from older adults, can improve prediction of incident cognitive impairment and dementia. To test these Specific Aims, we have assembled a multidisciplinary team with expertise in AD, neuroimaging biomarkers (amyloid and tau), fluid biomarkers (CSF and blood), naturalistic driving, spatial navigation, cognitive and brain aging, and longitudinal biostatistical methods. We will capitalize on existing institutional infrastructure to longitudinally follow 300 cognitively normal older adults and 50 older adults with mild or very mild dementia, to create a cohort of 350 individuals. This cohort will be followed using a naturalistic driving methodology that will capture their driving behaviors on a daily basis. Their cognition will be tested annually using the Clinical Dementia Rating and various neuropsychological measures. Once obtained, this knowledge can be used to map driving as a neurobehavioral biomarker that may be monitored and used for clinical trials and interventions throughout disease pro...