Neurodegenerative diseases are the most predominant brain disorders worldwide, and the affected populations are rapidly increasing. The selective vulnerability of a specific neuronal population followed by progression to higher cortical areas is the most distinct factor in disease conditions. The primary cause for vulnerability is still unclear. In the initial stages of Alzheimer's disease (AD), hippocampus neurons located in the temporal lobe are more vulnerable to cell death than other neuronal populations. Transcriptome and associated pathway analysis of this vulnerable region may shed light on selective vulnerability.

This study explored the transcriptome data obtained from various cerebral lobes and identified UTR variants from temporal, frontal, and other lobes of AD. These variants affect the conserved binding motifs of transcription factors (TF) and miRNA. From the results, we propose that abnormalities in astrocyte structural integrity and glia-neuron communication affect the energy craving neuron, and these events lead to energy imbalance.

We have standardized the pipeline for variant and differential gene expression analysis using brain RNA seq data. The performance of existing tools is evaluated based on gold standard dataset (mainly for cancer) using hg19 but not with recent hg38 annotation. We found that transcriptomic-based gene quantification showed better results compared to genomic alignment-based quantification. This study revealed a high number of reads mapped to multiple genome locations with hg38 than hg19, and these spurious multi-mapped reads may affect the gene quantification techniques.

Further, we identified variants, differential genes and transcript expression profiles from hippocampus RNA-seq data. We predicted the effect of variants in transcription factor (TF) binding using in silico tools. A hippocampus-specific co-expression and functional interaction network are designed to decipher the relationships between TF and differentially expressed genes (DEG). Identified variants predominantly influence TF binding, which subsequently regulates the DEG. From the results, we hypothesize that the loss of vascular integrity is the fundamental attribute of the energy crisis, which leads to neurodegeneration.

Since Alzheimer's (AD) and Parkinson's (PD) diseases share common pathological and symptomatic etiologies, analyzing the affected tissue in both disorders may help to recognize potential drug targets. Brodmann Area 9 (BA9) plays a crucial role in cognitive skill, executive memory, and motor behavior, and patients with AD and PD showed impairment in these skills. Analyzing BA9, we found that vascular smooth muscle and endothelial pathway-related genes are dysregulated in AD and PD. The large-scale network and gene signature analysis revealed that MAPK1, FGFR1, and FLT1 are promising therapeutic targets for AD and PD. These targets need to be evaluated for therapeutic intervention to reduce vascular permeability and neuroinflammation using experiments.