ALZHEIMERS RESEARCH PROJECT: Developing Extraceullar Vesicle biomarkers for clinical and preclinical AD/ADRD

National Institute On Aging

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Abstract

The Human Neuroscience Section pioneered biomarker studies using blood Extracellular Vesicles (EVs) enriched for neuronal origin (isolated by immunoaffinity capture targeting neuronal surface markers, such as L1CAM, and more recently NLGN3 and GAP43), or astrocytic origin (isolated by immunoaffinity capture tarheting astrocytic surface marker GLAST). To date, we have conducted scores of case control studies measuring EV-associated beta-amyloid, tau and p-tau species, Ser and Tyr phosphorylated IRS-1, synaptic markers, mitochondrial proteins, and various intracellular signaling mediators, and demonstrating differences between individuals with clinical and preclinical Alzheimer's disease and related dementias (AD/ADRD) and controls. We have found multiple disease-associated differences that, for some proteins, may effectively discriminate between the two populations. In addition, by analyzing samples from large preclinical cohorts, such as the Baltimore Longitudinal Study on Aging, the Wisconsin Registry for Alzheimer's Prevention and the Women's Health Initiative Memory Study, we have found biomarker abnormalities present at the preclinical stage that may predict future cognitive decline and future ADRD diagnosis. We are working on further demonstrating the relationship between between EV markers and other biomarkers for AD (PET, MRI) in longitudinal cohorts. We published results from a large cohort of participants in the Women's Health Initiative Memory Study - Long Life Study with and without cognitive resilience and with and without APOE ε4 genotype. We showed that resilient ε4 carrier women had higher baseline levels of phosphorylated TNFR1, NFκB, c-Myc, and FADD than ε4 carriers who eventually developed impairment at > 80 or ≤ 80 years. Additionally, resilient ε4 carrier women had higher baseline mitochondrial Complex V levels than ε4 carriers impaired at age > 80. In addition, we are examining the relationship of EV biomarkers with cognitive performance and amyloid and tau PET deposition using the longitudinal cohort of CHARIOT-PRO. A main focus for this coming year will be the analysis of samples from the Diabetes Prevention Program Outcomes Study (DPPOS), as well as samples shared by collaborators at the University of Southern California. We are continuously expanding the use of EV biomarkers in other neurological and psychiatric disorders that share mechanisms with AD/ADRD, demonstrating their diagnostic and disease-monitoring potential in Parkinson's disease (PD), Multiple Sclerosis, Traumatic Brain Injury, Restless Legs Syndrome, Covid-19 infection / long COVID with neurological abnormalities, Fragile X Ataxia Tremor Syndrome, but also psychiatric disorders, such as Bipolar Disorder, and Schizophrenia. We have recently demonstrated abnormalities in EV-associated mitochondrial cargo and synaptic proteins in Multiple Sclerosis, mitochondrial abnormalities in Fragile X Ataxia Tremor Syndrome pre-mutation carriers, and iron regulatory proteins in Restless Legs Syndrome. We have had the opportunity to review our and others' work on EV biomarkers in Neurology and present our vision for the future in a comprehensive review article published by Nature Reviews Neurology.