Nicholas Fitz

Research to characterize the Alzheimer's Disease Exposome will address major gaps in understanding of how environmental factors interact with genetic factors to increase or reduce risk for the disease across individual age and duration of exposure. We know that increasing age is the most important risk factor for Alzheimer's disease, but many other risk factors including environmental exposures are poorly understood. The importance of environmental factors in gene-environment interactions is suggested by wide individual differences in cognitive loss and pathology progression, particularly among people who carry genes that increase the risk of Alzheimer's disease. Among carriers of APOE4, few people never develop the disease, suggesting environmental risk as contributing to that variability. A recent study showed that environmental factors including exposure to air pollution and low socioeconomic status shifted the onset by ten years in a cohort of familial Alzheimer's disease patients. The proposed AD exposome includes macrolevel external factors such as living in rural versus urban areas, along with individual external factors such as toxicant exposures, diet, exercise and infections. These exogenous domains can overlap and interact with endogenous factors including individual fat deposits, hormones, and brain injury. To further develop an Alzheimer's disease "roadmap" of modifiable factors in brain aging and dementia, we are exploring how the exposome, with low level arsenic exposure as a model, impacts the normal function of neurons, microglia and astrocytes through assessing changes in the cell specific epigenome, homeostatic functions, and lipid transport. We hypothesize that exposures, either during important developmental windows or during long periods of one's life, will influence normal neural functions which could predispose to AD or accelerate the disease progression.

A complementary and increasingly central component of my work examines extracellular vesicles (EVs) as both a mechanism and a readout of these exposure-driven changes. EVs are nanoscale, membrane-bound carriers of proteins, lipids, and small non-coding RNAs (ncRNAs) that mediate intercellular communication, and their cargo reflects the physiological and pathological state of the cell of origin, making them a natural window into how the exposome reshapes signaling among neurons, microglia, and astrocytes. We have shown that small nucleolar RNAs (SNORDs), including the imprinted SNORD115 and SNORD116 clusters at chromosomal region 15q11-q13, are enriched in the plasma EVs of Alzheimer's disease patients relative to cognitively normal individuals and discriminate between the two groups with high accuracy, with enrichment that differs by APOE genotype. This directly connects peripheral EV signatures to the APOE-linked variability described above. In preclinical models, we have generated a multi-compartment atlas of tauopathy-associated transcriptional signatures across brain tissue and plasma EVs, identifying circular RNA cargos that track pathology, and we have developed and validated an open-flow microdialysis technique for sampling brain-derived EVs directly from interstitial fluid in wild-type and APP/PS1 mice, enabling monitoring of disease- and exposure-associated changes in brain EV cargo in vivo. We have further demonstrated that circulating EVs are functionally consequential: EVs from young serum are required for the restoration of age-related brain transcriptomes and the improvement of cognition in aged mice, and serum EV cargo serves as a biological indicator of resilience in older adults. Together, these findings position EVs as an accessible, cell- and compartment-specific biomarker platform for tracking how environmental exposures act on the brain across the life course, and as a candidate mediator of the systemic "lung-brain" and "renal-brain" axes central to the exposome model.

I have a broad background in the use of transgenic animal models, transcriptomics, microscopy, molecular genetics, cellular and molecular biology, and the isolation and small non-coding RNA profiling of extracellular vesicles from plasma, serum, and brain interstitial fluid, with specific training and expertise in molecular pathogenesis and experimental therapy for neurodegenerative disease and neuroinflammation.