TDP-43 pathological inclusions are associated with a spectrum of clinical syndromes including behavioral variant frontotemporal degeneration (bvFTD), primary progressive aphasia (PPA), or amyotrophic lateral sclerosis (ALS). Moreover, approximately 10% of bvFTD or PPA patients share neuromuscular features of ALS (ALS-FTD). Beyond the clinical complexities of the FTD and ALS spectrum associated with TDP-43, there are also many shared genetic links between these conditions including C9orf72 repeat expansions and TARDBP mutations that can result in bvFTD and/or ALS as well as disparate genetic mutations that exclusively result in FTD (e.g., GRN) or ALS (e.g., SOD1). The overall hypothesis of this project is that molecular heterogeneity, and specifically regionally-variable gene expression, contributes to macroscale network vulnerability contributing to a spectrum of clinically heterogeneous syndromes. It is critical to better understand the neuroanatomic and clinical features of gene expression in the current era of precision medicine in which there are antisense oligonucleotide (ASO) and adeno-associated vector (AAV) viral genetic therapies that aim to modify gene expression which have recently received FDA-approval for neuromuscular disorders and are underway for C9orf72 and GRN. While prior studies suggest that genetic and epigenetic variation contributes to the spectrum of heterogeneity in FTD and ALS, evaluations of the relationships between gene expression and disease phenotype are rare. This project aims to establish biological and genetic factors that influence regional anatomic disease burden which will provide regionally-specific biomarkers to track in emerging genetic therapies. We propose three Specific Aims: (1) Identify regional relationships between molecular gene expression and macroscale networks that bias risk for a specific clinical syndrome. We will interrogate publicly- available regional RNA microarray data and relate patterns of covariance from TDP-associated genes to structurally and functionally-derived networks that are associated with distinct bvFTD, PPA, and ALS syndromes; (2) Establish convergence between gene expression and in vivo neuroimaging networks of FTD and ALS patients. We will relate regional RNA microarray data of healthy individuals to in vivo cortical thickness and graph-theoretic network features (e.g., degree, path length) defined in Core E that are derived from FTD and/or ALS patients with inherited disease recruited from Core B and scanned using 3T MRI in Core C. We hypothesize that the regional distribution of gene covariance in typical adults will relate to the regional distribution of neurodegeneration in individuals with genetic mutations; and (3) Determine the manner in which modifiers of gene expression impact network structure in FTD & ALS. Using principles of network control theory we will leverage naturally-occurring heterogeneity in gene expression, including epigenetic (e.g., DNA methylation) and common genetic (e.g., allele dosage) factors, to determine whether these gene enhancing or silencing sources of heterogeneity are associated with altered network distributions of disease.