PROJECT SUMMARY Patients with rapidly progressive dementia (RPD) experience accelerated declines in cognition resulting in dementia within 1 year or complete incapacitation within 2 years of symptom onset. Although the medical literature has long emphasized the contributions of Creutzfeldt-Jakob disease to RPD, rapidly progressive forms of Alzheimer disease and AD-related dementias (rpAD/ADRD) account for most cases of RPD in older individuals. The rapid rate of decline in patients with rpAD/ADRD presents a great clinical challenge for the assessing clinician but also a unique opportunity to study the biological factors that underlie this extreme endophenotype across a shortened symptomatic period. The Biomarkers and Rates of Progression in Dementia (Bio-RaPID) study will capitalize on this opportunity by enrolling and evaluating 120 patients with rpAD/ADRD. Recruitment will be supported by a 9-site referral network engaging 7 Alzheimer Disease Research Centers with expertise in recruitment of underrepresented groups. Structured clinical evaluations will be conducted at baseline, 12-, and 24-months at Mayo Clinic Jacksonville (FL) or Rochester (MN). Interval telemedicine assessments with remote blood collection at 3- and 6-months will minimize participant burden while enabling serial measures of cognitive function and blood-based biomarkers. In this way, Bio-RaPID will combine clinical expertise, validated diagnostic approaches, long-read whole genome sequencing, and gold-standard in vivo measures of amyloid (A: CSF ptau181/Aβ42), tau (T: flortaucipir PET), neurodegeneration (N: MRI), cerebrovascular disease (V: MRI), pathologic aggregates of α-synuclein (CSF seed amplification assay), and biofluid biomarkers of neuroinflammation to determine the patient- and disease-specific factors that contribute to rpAD/ADRD. Use of ADRC protocols and coordination with ADRC Cores will enable comparison with existing patients with typical AD/ADRD and broad sharing of Bio-RaPID data. This “whole patient, whole brain” approach will inform the influence of patient-specific factors on rpAD/ADRD susceptibility, including age, sex, medical history, structural and social determinants of health, genetic variants, and ATN(V) and α-synuclein pathology (Aim 1); and the contributions of disease-specific factors to disease progression, including burden and topology of neuropathology and the mediating effects of neuroinflammation (Aim 2). Finally, Bio-RaPID will leverage unbiased proteomic analyses in CSF from an independent cohort of patients with autopsy-confirmed rapid and typical AD/ADRD (n=120, each) to validate findings from Aim 1 and 2 and identify cellular/protein pathways that are uniquely expressed or altered in rpAD/ADRD (Aim 3). Bio-RaPID aims will inform the cumulative contributions of demographics, concurrent health issues, structural and social determinants of health, genetics, biofluid biomarkers, and ATN(V) neuropathology to cognitive decline and synaptic d...