Project Summary/Abstract Alzheimer’s disease and related dementias (ADRDs) are highly prevalent, devastating to patients and their loved ones, and encompass a diversity of etiologies and pathologies. Traumatic brain injury (TBI) and repetitive head impacts (RHI) can contribute to the initiation and/or acceleration of ADRDs, including chronic traumatic encephalopathy (CTE), but critical gaps in knowledge prevent the development of effective diagnostic strategies and therapeutic interventions. Most importantly, mechanisms through which diverse patterns of head trauma increase risk for AD/ADRD/CTE are not known, nor is it clear how multiple pathological processes interact to influence symptom manifestation and disease progression. These knowledge gaps must be addressed to enable in vivo diagnosis and disease-modifying therapeutics in our lifetime - the highest-priority recommendation for post-TBI AD/ADRD from the 2022 ADRD Summit. To address these critical issues, we propose NEW-HOPE-TBI, a unique and powerful cohort and open-access biospecimen, imaging, and data resource to enable and enhance research to better understand connections between macroscopic (neuroimaging) and microscopic (neuropathology) features of posttraumatic AD/ADRD/CTE. To accomplish this, we propose to expand our existing nationwide network of well-characterized brain donors from diverse cohorts with heterogeneous TBI exposures and/or AD/ADRD (Aim 1), broadly characterize co-pathology burden about head trauma (HT) exposure patterns (Aim 2), identify quantitative neuropathology and imaging signatures of cognitive and behavioral decline in chronic TBI and post-traumatic neurodegeneration (Aim 3), and deeply phenotype meso- to micro- scale vascular pathology in TBI (Aim 4). Through this work, we will build a unique open-access biospecimen and data biorepository that includes digital pathology and imaging data linked to accessible brain tissues and biofluids, and critical metadata including TBI exposure history, cognitive and behavioral health metrics, and social determinants of health, from well-characterized research donors (Aim 5). We have assembled a world-class team of scientists, clinicians, neuroimagers, neuropathologists, and biostatisticians to fulfill the goals of this proposal, including Dr. Tim Brown, a bioethics expert who is committed to advising NEW-HOPE-TBI concerning diversity, equity, and inclusion in our research team and cohort. Finally, to promote AD and ADRD neuropathology research far into the future, we place great emphasis on the career development and engagement of junior neuropathologists and fellows who represent the next generation of post-traumatic neurodegenerative neuropathology researchers. The proposed work is made possible by leveraging clinical TBI and AD/ADRD studies, network-based autopsy with ex vivo MRI, postmortem data that far exceed the NIH CDEs, a world-class team of senior, mid-level, and early-stage investigators, and a unique focus on neuroethics to enhance diversity in neuropathology research. No other team in the world can lead the science and data sharing proposed herein.

Project Narrative Alzheimer’s disease and related dementias (ADRD) are prevalent, afflicting more than 50 million Americans directly and countless additional family members and caregivers, and devastating. Understanding the relationship between/mechanisms underlying posttraumatic neurodegeneration is critical to diagnosing and treating afflicted patients more effectively. NEW-HOPE-TBI will develop and enhance a world-class brain tissue and open-access digital resource that combines deep clinical phenotyping, advanced neuroimaging, and state-of-the-art multimodal neuropathology from diverse prospective and observational cohorts across the spectrum of TBI-exposed and unexposed AD and ADRD donors to propel impactful posttraumatic AD and ADRD research.