Biobehavioral Signatures of Repetitive Head Impacts at the Intersection of Aging and Alzheimer's Disease - ABSTRACT Millions of older adults are at increased dementia risk because of prior exposure to repetitive head impacts (RHI), such as those from contact sports, military service, intimate partner violence, and other sources. Investigating common, globally relevant, environmental dementia risk factors like RHI is a public health imperative. We lack a fundamental understanding of how RHI leads to cognitive decline, including the distinct biological pathways and brain regions that are disrupted. Further, the intersection of prior RHI with common diseases of aging, such as Alzheimer’s disease (AD), cannot be ignored given the potential for a synergistic negative impact on brain health. Progress towards accurately identifying (diagnosis) and effectively treating RHI-related brain changes depends on defining key molecular and brain structure correlates of RHI. Our multi-site, multidisciplinary team is uniquely positioned to address these critical gaps and make substantial strides towards precision care for aging adults with prior RHI. This proposal builds directly on our strong portfolio of published research and compelling preliminary data pointing us towards the importance of 1) altered inflammation and immune-signaling pathways and 2) vulnerability of limbic system structures seen several years downstream of RHI, distinct from the effects of AD, and potentially explaining later-onset of RHI-related cognitive decline. We aim to accelerate our recent progress through a longitudinal study of fluid biomarkers, neuroimaging, and cognition in aging adults with and without RHI to parse RHI effects on brain aging (i.e., RHI “signatures”). In this R01 from an Early-Stage Investigator (ESI), we will investigate intersections of aging, RHI, and AD using the collective infrastructure of 3 ADRCs (1Florida, Boston University, University of California-San Francisco). We will identify data-driven molecular (plasma proteomics; Aim 1) and brain structure (multimodal MRI; Aim 2) signatures of RHI and map onto cognitive trajectories (Aim 3). The primary cohort will be strategically sampled to study 400 older adults with representation across the RHI, AD pathology, and cognitive continuums. Robust validation of our findings will be performed two ways: 1) internal validation – longitudinal subset within the primary study cohort, 2) external validation – independent sample enriched for RHI across the cognitive and AD pathology continuum (DIAGNOSE-CTE II). Our methods are conceptually and technically innovative: multi-site gold standard head trauma measurement integrated with deep clinical and biological phenotyping, Subtype and Stage Inference modeling (SuStaIn), large-scale proteomics and bioinformatics from ~11,000 proteins (SomaScan®), leading- edge brain MRI (hippocampal subfield analysis, free water diffusion), and modeling the full continuum of RHI exposure. Executing this ESI-led project will provide foundational knowledge of the relationships between RHI, AD, and aging. Identifying RHI-related molecular targets, brain atrophy and white matter injury patterns, and cognitive correlates are essential steps for understanding mechanisms, accurately modeling disease progression, and developing interventions for millions of at-risk older adults with prior RHI.
