Defining early changes in Alzheimer's disease from RNA sequencing of brain regions differentially affected by pathology

Tau pathology in Alzheimer's disease (AD) spreads in a predictable pattern that corresponds with disease symptoms and severity. At post-mortem there are cortical regions that range from mildly to severely affected by tau pathology and neuronal loss. A comparison of the molecular signatures of these differentially affected areas within cases and between cases and controls may allow the temporal modelling of disease progression. Here we used RNA sequencing to explore differential gene expression in the mildly affected primary visual cortex and moderately affected precuneus of ten age-, gender- and RNA quality-matched post-mortem brains from AD patients and healthy controls. The two regions in AD cases had similar transcriptomic signatures but there were broader abnormalities in the precuneus consistent with the greater tau load. Both regions were characterised by upregulation of immune-related genes such as those encoding triggering receptor expressed on myeloid cells 2 and membrane spanning 4-domains A6A and milder changes in insulin/IGF1 signalling. The precuneus in AD was also characterised by changes in vesicle secretion and downregulation of the interneuronal subtype marker, somatostatin. The 'early' AD transcriptome is characterised by perturbations in synaptic vesicle secretion on a background of neuroimmune dysfunction. In particular, the synaptic deficits that characterise AD may begin with the somatostatin division of inhibitory neurotransmission.

Automated summary

Tau pathology in Alzheimer's disease follows a predictable pattern corresponding to disease symptoms and severity. Comparing molecular signatures in differentially affected areas may help in modelling disease progression. RNA sequencing in AD brains showed similarities in transcriptomic signatures between mildly and moderately affected regions, with broader abnormalities in the latter due to greater tau load. Both regions exhibited upregulation of immune-related genes, with additional changes in vesicle secretion and neuronal markers in the moderately affected precuneus. Early AD transcriptome is characterized by perturbations in synaptic vesicle secretion and neuroimmune dysfunction.