We generated RNA-seq data from brains carrying pathogenic mutations in APP, PSEN1, and PSEN2, which cause alterations in Aβ processing and lead to ADAD, and also generated RNA-seq from brains of LOAD and neuropath-free controls. We observed altered cell composition in both ADAD and LOAD compared to controls. However, we identified that ADAD brains have a different cell-type composition than disease-stage-matched LOAD, as the ADAD has a significantly lower relative neuronal proportion and more pronounced astrocytosis. Given the specific cellular population structure of the TREM2 carriers, we compared the neuronal and astrocytic relative proportion of ADAD to that of LOAD non-carriers of variants in TREM2 and observed significant differences (β = − 0.09 and p = 6.89 × 10−03 for neurons and β = 0.10; p = 1.49 × 10–03 for astrocytes). This indicates that the difference of the relative proportion between ADAD and LOAD are not driven by TREM2 carrier brains. Based on our results, we would hypothesize that this change in Aβ processing of ADAD would lead to more direct to neuronal death than the pathological processes of
