Extraceullar Vesicle Biomarkers for Prediction of Cognitive Decline, Ab and TAU Accumulation, and atrophy in Preclinical Alzheimer's Disease

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In previous studies, our section pioneered a methodology capturing blood Extracellular Vesicles (EVs) enriched for neuronal origin (achieved by immunoaffinity capture using neuronal surface markers, including, but not limited to, L1CAM), or astrocytic origin (achieved by immunoaffinity capture using astrocytic surface marker GLAST). To date, we have conducted scores of case control studies measuring EV-associated beta-amyloid, tau/p-tau, Ser and Tyr phosphorylated IRS-1, synaptic markers, mitochondrial proteins and other signaling mediators, in AD and control subjects. We have found multiple disease-associated differences that, for some proteins, may effectively discriminate between the two groups. In addition, biomarker abnormalities may be present at the preclinical stage and may predict AD. We recently showed that EV biomarkers predict future cognitive decline and future AD diagnosis in large preclinical cohorts from the Baltimore Longitudinal Study on Aging, the Wisconsin Registry for Alzheimer's Prevention, and the Atherosclerotic Risk in Communities studies. This project is seeking to further demonstrate the relationship between EV markers and other biomarkers for AD (especially amyloid and Tau PET, and MRI atrophy) in large preclinical cohorts. These studies are needed to assess longitudinal changes in EV markers and their potential to predict AD at the preclinical stage, track disease progression and predict conversion from MCI to AD. We are in the process of analyzing samples from a large cohort of participants in the Women's Health Initiative Memory Study - Long Life Study to assess the relationship of EV biomarkers with cognitive resilience in women and APOE e4 genotype. In addition, we have analyzed samples of individual with young-onset vs. older-onset AD from the Indiana ADRC. In the coming year, we will produce EV biomarker measurements and examine their relationship against cognitive performance, amyloid and tau PET deposition, MRI atrophy and clinical progression from MCI to AD dementia using longitudinal cohorts (Harvard Aging Brain Study and CHARIOT-PRO).