Discovery and Trial Ready Cohort for Limbic Predominant Age Related TDP-43 Encephalopathy (TRC LATE) - ABSTRACT Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a common pathological change that significantly contributes to cognitive decline in older adults and plays a critical role in Alzheimer’s-type dementia in older age groups. LATE-NC is prevalent in over one-third of participants and half of dementia decedents in aging cohorts, often mimicking Alzheimer’s disease neuropathologic change (ADNC) with an amnestic presentation. LATE-NC and ADNC frequently coexist, leading to multiple-etiology dementia (MED). Despite recent progress in efforts to establish diagnostic criteria for LATE, significant gaps remain in validation of diagnostic criteria, LATE biomarkers, and recruitment strategies for early-phase clinical trials targeting LATE-NC. This project aims to address these unmet needs by creating a Discovery and Trial Ready Cohort for LATE (TRC LATE) through recruiting and characterizing 420 participants aged 85 and older across five Alzheimer’s disease research centers (ADRCs). These participants will undergo comprehensive annual assessments, including neuropsychological testing, annual brain MRI, FDG-PET scan every 2 years, annual blood collections, remote cognitive assessments, and recruitment science experiments. Approximately 200 of the participants who fulfill the current LATE diagnostic criteria will be enrolled in the Trial-Ready Cohort for enrollment in future early phase trials of LATE. The study aims to validate clinical, neuropsychological, and imaging markers for LATE (Aim 1), identify novel biomarkers and develop risk scores for LATE-NC (Aim 2), and conduct trial planning and recruitment science studies, which will focus on identifying barriers to participation in clinical trials and evaluating methods to improve understanding and willingness to engage in LATE and LATE/AD combination trials (Aim 3). By establishing this diverse, well-characterized cohort, we will generate crucial data to accelerate early-phase clinical trials targeting LATE-NC, discover new biomarkers, and develop new strategies for recruiting traditionally underrepresented populations in ADRD research. Ultimately, this study will reduce trial timelines and enhance our understanding of the clinical complexities of aging-related dementias. 1
