Thursday, November 21, 2024
11/21/2024
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 dysfunction in rpAD/ADRD. In turn, these findings will be extended to identify biomarkers and novel treatment targets with the potential to arrest or slow pathologic progression in patients with rapid and typical progressive AD/ADRD.
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