Emerging research implicates gait dysfunction as a preclinical marker of Alzheimer’s disease and related dementias. Our team has been in the vanguard of gait and cognition research. To advance the field, we will employ innovative gait phenotyping and multidisciplinary team science approaches to discover novel risk and protective mechanisms for gait dysfunction in the context of dementias. The aging population can be classified into slow-movers (1SD below ‘robust’ mean speed for age and sex), usual-movers ( 1SD) and fast-movers (≥1SD). We will employ novel multi-modal neuroscience, neurophysiological, and biological approaches to discover novel risk mechanisms in the earliest stages of gait and cognitive decline (preceding slow mover stage). We introduce the original concept of ‘super-movers’: non-demented and non-disabled fast movers, 80 years and older with gait speed of adults 30 years younger. We posit that this unique group of oldest fast movers are enriched in unique brain and biological profiles that help maintain exceptional gait into their 9th decade, and will provide a window into protective mechanisms. We hypothesize that the interplay between pathological and resilience mechanisms in aging results in structural, functional, and neurophysiological brain changes leading to the emergence of gait dysfunction as a preclinical marker of dementia. Aim 1: Identify protective brain mechanisms linked to gait in super-movers. We predict that compared to usual movers (≥80y): 1A: Super-movers will have better brain health on multi-modal measures. 1B: Super- movers will show differential activation over premotor and sensorimotor cortex sustained across the gait cycle in response to complex gait demands. 1C: As some (but not all) fast-movers will age into super-movers, we will compare neuroimaging and mobile EEG measures in fast-movers vs usual/slow movers in all participants (≥65y). Aim 2. Establish neurophysiological mechanisms underlying gait and cognitive decline in aging. In the overall sample (≥65y): 2A: Baseline gait related mobile EEG activation patterns will predict longitudinal declines in cognition as well as combined cognitive-motor decline. 2B: Poor multisensory integration at baseline will predict longitudinal declines in cognition and Motoric Cognitive Risk syndrome. Aim 3. Determine pathological mechanisms underlying gait and cognitive decline in aging. We predict among adults ≥65y: 3A: Slow movers will have more, and faster movers will have less neurodegenerative pathology (p-Tau, Aß-42 and NFL) than usual movers. 3B: Higher levels of neurodegenerative pathology at baseline will predict cognitive decline and Motoric Cognitive Risk syndrome. This proposal is highly responsive to RFA-AG-24-041. Successfully attaining our aims will inform the use of gait as an early ‘cognitive’ biomarker, identify protective mechanisms that promote resilience to Alzheimer’s disease and related dementias, and guide the design of early interventions to prevent cognitive decline.

Narrative Emerging research implicates gait dysfunction as a preclinical marker of Alzheimer’s disease (AD) and related dementias (ADRD). Building on our research, we will employ a team science approach with multi-modal neuroscience and biological methods to examine mechanisms underlying gait and cognitive decline in aging. Our overall hypothesis is that the interplay between pathological and resilience mechanisms in aging results in structural, functional, and neurophysiological brain changes that lead to the emergence of gait dysfunction as a preclinical marker of dementia.