Abstract
Alzheimer's disease is a progressive neurodegenerative disorder associated with memory loss and impaired executive function. The molecular underpinnings causing cognitive deficits in Alzheimer's disease are loosely understood. Here, we performed cross-study large-scale transcriptomic analyses of postmortem prefrontal cortex derived from Alzheimer's disease patients to reveal the role of aberrant gene expression in this disease. We identified that one of the most prominent changes in prefrontal cortex of Alzheimer's disease humans was the downregulation of genes in excitatory and inhibitory neurons that are associated with synaptic functions, particularly the SNARE-binding complex, which is essential for vesicle docking and neurotransmitter release. Comparing genomic data of Alzheimer's disease with proteomic data of cognitive trajectory, we found that many of the lost synaptic genes in Alzheimer's disease encode hub proteins whose increased abundance is required for cognitive stability. This study has revealed potential molecular targets for therapeutic intervention of cognitive decline associated with Alzheimer's disease.