Abstract Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) 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, FTLD and ALS 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, in Aim 1, we systematically profile the transcriptional and epigenomic alterations of FTLD and ALS patients at single-cell resolution using post-mortem brain samples. In Aim 2, we integrate the resulting datasets to study the link between genetic, epigenomic, transcriptional, and cellular signatures of FTLD and ALS, and to study the common and distinct genes and pathways altered in each, to predict new therapeutic targets. In Aim 3, we validate the molecular and cellular effects of these targets using high-throughput directed perturbation experiments and both cell-autonomous and non-autonomous phenotypes guided by our predicted pathways, and we disseminate all our results to the community. The resulting datasets, analyses, and validated targets will provide an invaluable resource to understand the mechanisms of action of FTLD and ALS, and the common and unique circuitry towards new therapeutic targets.