ABSTRACT Identification of novel, non-cognitive (i.e., sensory or motor), non-invasive markers of Alzheimer’s disease and related dementias are a national priority identified by the National Alzheimer Plan. Growing evidence suggests that Alzheimer’s pathology manifests in sensory association areas well before appearing in neural regions involved in memory function. Previous investigations have failed to examine the interplay and time course of sensory, cognitive, and motor dysfunction on the progression of Alzheimer’s disease. The ability to successfully integrate multisensory information across multiple sensory modalities is a vital aspect of functioning and mobility in the real world. Our research suggests that multisensory integration could be used as a novel marker for preclinical Alzheimer’s disease given reported associations between magnitude of visual-somatosensory integration and important cognitive (attention) and motor (balance, gait, and falls) outcomes. We have highlighted the adverse effects of dementia and mild cognitive impairment on these relationships, but the underlying functional and neuroanatomical networks remain to be uncovered. Identification of these functional networks is critical to guide development of future multisensory-based interventions to prevent non-cognitive outcomes such as falls in cognitively impaired individuals. Hence, we propose to recruit 208 community-dwelling older adults with and without preclinical Alzheimer’s disease (defined as impaired cognitive function on neuropsychological testing and presence of Aß in plasma) for a three-year longitudinal observational study. Our central hypothesis is that preclinical Alzheimer’s disease is associated with neural disruptions in subcortical and cortical areas that concurrently modulate multisensory, cognitive, and motor functions, resulting in mobility decline. Our strategic experimental design, which leverages existing longitudinal cohorts, aims to assess the validity of multisensory integration as a behavioral marker for preclinical Alzheimer’s disease. It also provides an opportunity to examine the integrative time course and interplay of individual sensory, motor, and cognitive processes (and their interactions) in preclinical Alzheimer’s disease. The proposed project addresses the NIH’s priority, as well as NIA’s special interest notice [NOT-AG-20-053]. This work will increase understanding of the neurobiology of Alzheimer’s disease and will guide future multisensory-based intervention studies that aim to alleviate disability and maintain independence in older adults with and without preclinical Alzheimer’s disease. 2

NARRATIVE We propose a novel, non-cognitive, non-invasive behavioral marker of preclinical Alzheimer’s disease called multisensory integration based on findings that reveal a functional interplay of multisensory, cognitive, and mobility processes. Our proposed study will: 1) provide a deeper understanding of the functional neural networks involved in multisensory integration processes in preclinical Alzheimer’s disease; 2) determine whether functional multisensory activation in prefrontal cortex predicts future mobility decline and falls in preclinical Alzheimer’s disease; 3) assess the validity of multisensory integration as an early marker for preclinical Alzheimer’s disease; and 4) provide insights into the neurobiology of Alzheimer’s disease. Results from this project will guide future multisensory-based interventions aimed to alleviate disability and maintain functional independence of older adults at-risk for Alzheimer’s disease that can significantly augment existing interventions. 1