Endotype Characterization Reveals Mechanistic Differences Across Brain Regions in Sporadic Alzheimer’s Disease

Background: While Alzheimer’s disease (AD) pathology is associated with altered brain structure, it not clear whether gene expression changes mirror the onset and evolution of in distinct regions. Deciphering mechanisms which cause differential manifestation across different regions has potential to help early diagnosis. Objective: We aimed identify common unique endotypes their regulation tangle-free neurons sporadic AD (SAD) six regions: entorhinal cortex (EC), hippocampus (HC), medial temporal gyrus (MTG), posterior cingulate (PC), superior frontal (SFG), visual (VCX). Methods: To decipher states human subjects afflicted AD, we performed analysis neural transcriptome. explored expression, functional transcription factor target enrichment, co-expression module detection discern disease-state transcriptomic variances characterize endotypes. Additionally, compared our results tangled neuron microarray-based study Allen Brain Atlas. Results: identified impaired function EC, MTG, PC, VCX resulting from REST activation reversal mature a precursor-like state SFG linked SOX2 activation. decreased increased dedifferentiation were SUZ12. Energetic deficit connected NRF1 inactivation was found HC, VCX. Conclusions: Our findings suggest that SAD varies scale severity endotypes, such as energetic shortfalls, neuronal function, dedifferentiation.