Disparate and shared transcriptomic signatures associated with cortical atrophy in genetic bvFTD

Abstract

Cortical atrophy in behavioral variant frontotemporal degeneration (bvFTD) exhibits spatial heterogeneity across genetic subgroups, potentially driven by distinct biological mechanisms. Using an integrative imaging-transcriptomics approach, we identified disparate and shared transcriptomic signatures associated with cortical thickness in C9orf72, GRN or MAPT-related bvFTD. Genes associated with cortical thinning in GRN-bvFTD were implicated in neurotransmission, further supported by mapping synaptic density maps to cortical thickness maps. Previously identified genes linked to TDP-43 positive neurons were significantly overlapped with genes associated with C9orf72-bvFTD and GRN-bvFTD, but not MAPT-bvFTD providing specificity for our associations. C9orf72-bvFTD and GRN-bvFTD shared genes displaying consistent directionality of correlations with cortical thickness, while MAPT-bvFTD displayed more pronounced differences in transcriptomic signatures with opposing directionality. Overall, we identified disparate and shared genes tied to regional vulnerability with increased biological interpretation including overlap with synaptic density maps and pathologically-specific gene expression, illuminating intricate molecular underpinnings contributing to heterogeneities in bvFTD.