Multi-omic integrative analysis of shared and distinct inflammation networks across neurodegenerative disorders - Summary/Abstract: Alzheimer's disease (AD) and frontotemporal disorder (FTD) are two of the most common neurodegenerative disorders, with limited available therapeutic options. Although they differ in terms of genes associations, underlying proteinopathy, and affected brain regions, they share pathological features such as increased inflammation and neuronal loss. Recent findings indicate that addressing inflammation might be a potential treatment for AD and FTD. Despite considerable evidence supporting the presence of peripheral and central chronic low-grade inflammation in AD and FTD, a comprehensive molecular understanding of inflammatory cascades and networks across these disorders is lacking. This knowledge gap represents a significant barrier to advancing the field. Our preliminary analysis of inflammation-related analytes from AD, FTD, and healthy control sera, identified the activation of specific inflammatory analytes and signaling nodes in both AD and FTD. In addition to the shared inflammatory signaling nodes, several disease-specific inflammatory analytes were altered in each neurodegenerative disorder. Based on our preliminary results, we hypothesize that the immune responses and activated inflammatory pathways in AD and FTD have shared and disease-specific characteristics and that it may be possible to identify novel interventional strategies for pan-neurodegeneration and disease-specific inflammatory responses. To confirm the preliminary findings and explore novel groups, we will perform a large-scale proteomic analysis to interrogate matched serum and CSF samples from 250 AD, 100 FTD patients and 150 age- and gender- matched healthy controls from two well-characterized national cohorts (Alzheimer's Disease Neuroimaging Initiative (ADNI) and ALL-FTD) (Aim 1). In the next step, we will evaluate the contribution of the altered inflammatory signals to AD and FTD changes. In this regard, we will investigate the association of inflammatory analytes and signaling nodes with 1) known genetic risk factors and mutations, 2) their sex-specific differences, 3) the correlation with relevant established biofluid biomarkers in AD and FTD, and 4) their impact on clinical outcomes (Aim-2). Finally, we will identify the neural and immune cell types responsible for the elevated inflammation in AD and FTD through single-cell RNA-sequencing and spatial transcriptomics (blood and brain tissue) analyses (Aim 3). This multi-omics integrative approach will offer novel insights into the mechanisms driving the peripheral and central inflammatory signals in AD and FTD and suggest treatment options. The innovation in this project results from the collaboration of multiple investigators with experience in neurodegeneration molecular immunology (Alireza Faridar, MD.), neuropathology, biomarkers, and data analysis (Jon B. Toledo, MD., PhD.), and single-cell analysis (Kyuson Yun, PhD.).
