Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating and fatal neurodegenerative diseases that strike middle-aged adults just as they reach full familial, financial and career potential. Initially thought to be quite distinct, ALS and FTD are now recognized to share many clinical, pathological, and genetic signatures, but the mechanistic basis of their shared and distinct circuitry remains unknown at the molecular level. Genome-wide association studies (GWAS) have uncovered multiple common weak-effect variants, but the vast majority are non-coding, making it difficult to identify their target genes and the cell types where they act. To address this challenge, we systematically profile the transcriptional and epigenomic alterations of ALS and FTD patients at single-cell resolution using post-mortem brain samples from ALS and FTLD patients (Aim 1). We integrate the resulting datasets to study the link between genetic, epigenomic, transcriptional, and cellular signatures of ALS and FTD, and to study the common and distinct genes and pathways altered in each, to predict new therapeutic targets (Aim 2). We validate the molecular and cellular effects of these targets using high-throughput directed perturbation experiments, and disseminate all our results to the community (Aim 3). The resulting datasets, analyses, and validated targets will provide an invaluable resource to understand the mechanisms of action of ALS and FTD, and the common and unique circuitry towards new therapeutic targets.