Tau A152T risk variant drives distinct cell type transcriptional signatures in AD and PSP.

The A152T point mutation is a rare genetic variant in the tau gene (MAPT) that is linked to risk of Alzheimer's disease (AD) and frontotemporal dementia spectrum disorders, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). To uncover mechanisms through which the A152T variant contributes to risk of tauopathy, we performed single-nucleus RNA sequencing (snRNA-seq) on postmortem brain tissue collected from A152T carriers and pathology-matched non-carriers with either AD or PSP, along with age-matched controls. These efforts revealed that despite similar cell type composition across groups, A152T carriers exhibited distinct cell type-specific transcriptional changes in both AD and PSP. Differential expression analysis identified excitatory neurons, oligodendrocytes, and astrocytes as the most affected cell populations in AD and PSP, and these same cell types showed the strongest A152T-specific changes. These findings identify transcriptional alterations that differentiate sporadic AD and sporadic PSP from AD-A152T and PSP-A152T, as well as shared molecular signatures unique to A152T carriers in both PSP and AD. Donor-level pseudo-bulk analyses showed broad directional support with the single-nucleus findings although the proportion of donor-supported genes varied across cell type and comparison. Importantly, merging sporadic and A152T cases into a single disease group was found to mask transcriptional differences in several cell types in both AD and PSP, indicating divergence in transcriptional signature and highlighting the importance of screening for genetic risk variants like A152T in snRNA-seq data from human cohorts.