Multiplex digital spatial profiling identifies subregion dependent targeted proteome changes across variants of dementia

Frontotemporal lobar degeneration (FTLD) is the leading cause of dementia in patients under the age of 65. Even in a single anatomical region, there is variance within pathological protein deposition within the FTLD spectrum, which drives difficulty in post-mortem clinicopathological diagnoses. We spatially multiplexed the proteome geography at two levels of the cortex and the subcortical white matter in patients with various types of dementia (Alzheimer's disease, C9orf72, MAPT also referred to as FTLD-tau, FTLD-TDP, FTLD-GRN; <i>n</i> = 6 per syndrome) and neurologically healthy controls (NHC). Layers II-V of the cortex from diseased individuals displayed the greatest protein dysregulation as compared to NHC. Traditional biomarkers of dementia, like phosphorylated tau proteins and Aβ42 displayed dysregulation, however, our data suggest spatial enrichment distinct to cortical sublayers. In conclusion, the specific localization of these protein deposits could be used to elucidate region-specific pathologic biomarkers unique to individual variants of dementia.