Proteo-transcriptomic analysis reveals brain-region-specific gene and biomarker expression in post-mortem neural tissue of Alzheimer’s patients

Abstract

AbstractAlzheimer’s disease is a neurodegenerative disorder, marked by dementia, impaired judgment, and a decline in cognitive abilities, that affects over 50 million people worldwide. The etiology of the disease is influenced by a myriad of genetic and environmental factors including APOE4 allele status and sex and can be characterized by a variety of neuropathological markers, such as amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs) in specific areas of the brain, as well as the dysregulation of certain genes. However, how APOE4 status and sex affect the expression of these biomarkers and the gene dysregulation patterns specific to each brain region have yet to be determined. In this study, statistical and correlational analyses were performed to identify and quantify the relationship between the expression of proteo-transcriptomic biomarkers associated with neurodegenerative disorders and neuronal development in the frontal white matter, parietal cortex, temporal cortex, and hippocampus with patient demographic and genetic information. Further analysis determined whether the observed correlations were brain-region-specific or sex-specific. There was a statistically significant relationship between APOE4 status and degree of Aβ accumulation (P < 0.001) and neurofibrillary tangle formation (P = 0.04). Aβ plaque deposition was found to be more severe in females (P = 0.001) and the intensity of Aβ and NFT formation differed across brain regions (P < 0.001, P = 0.001 respectively). Furthermore, transcriptomic analysis revealed brain-region-specific gene dysregulation patterns. These patterns can identify therapeutic targets for future targeted gene and protein therapies in specific brain regions to treat Alzheimer’s disease.