Homo sapiens Transcriptome or Gene expression. Homo sapiens

Tau pathology in Alzheimer's disease (AD) spreads in apredictable pattern that corresponds with disease symptoms and severity.At post-mortem there are brain regions that range from mildly to severelyaffected by neuritic plaques, neurofibrillary tangles, gliosis andneuronal loss. A comparison of the molecular signatures of thesedifferentially-affected areas within cases and between cases and controlsmay allow the temporal modelling of disease progression and identifyearly molecular changes in mildly affected areas. Here we used RNAsequencing to examine the mildly-affected primary visual cortex (VIC) andmoderately-affected precuneus (PREC) in ten age-, gender- and RNAquality-matched post-mortem brains from AD patients and healthy controls.AD-PREC was characterised by a greater tau pathology than the AD-VIC. Thetwo regions in the AD brain had transcriptomically similar changes butthese changes were more prominent in the PREC consistent with the greatertau load. AD-PREC was characterised by upregulation of immune-relatedgenes such as TREM2 and MS4A6A and downregulation of the interneuronmarker, somatostatin (SST). Digital PCR in a larger cohort of AD casesand controls confirmed the downregulation of SST in AD-PREC and in theAD-VIC. This study suggests that similar perturbations in immunesignalling and GABA-ergic neurotransmission occur in cortical regionsaffected by AD and that the magnitude of the response correlates withincreasing tau pathology. These systems represent early, therapeuticallyamenable, targets for intervention or potential biomarkers for diseaseprogression.