Unraveling metabolic pathways and key genes in Alzheimer’s, type 2 diabetes, and estrogen dysregulation among aging women: a systems biology approach

Alzheimer’s disease (AD) and Type 2 Diabetes Mellitus (T2DM) present significant global health challenges, particularly affecting aging women due to menopausal estrogen dysregulation. This study employs a systems biology approach to investigate the shared molecular pathways and key genes involved in AD, T2DM, and estrogen dysregulation.

We utilized the GeneCards database to identify common genes (CGs) among AD, T2DM, menopause, and estrogen dysregulation. RNA-seq data from normal aging women and those diagnosed with AD were analyzed for differentially expressed genes (DEGs). The shared genes (SGs) between DEGs and CGs from GeneCards were then mapped onto protein–protein interaction (PPI) networks using the STRING database. Topological analysis, including degree centrality and hub-bottleneck criteria, was performed using Cytoscape to identify key regulatory genes. Gene Ontology (GO) and KEGG pathway enrichment analyses were conducted to elucidate significant biological processes and pathways.

We identified 140 SGs between DEGs and CGs from GeneCards. These SGs were mapped onto a PPI network, revealing hub-bottleneck genes such as MAPK1, KRAS, GAPDH, ACTB, and HSP90AA1. These genes are integral to the Estrogen Signaling, PI3K-Akt, and Alzheimer's Disease pathways, involved in mechanisms like insulin resistance, neuroinflammation, and protein accumulation. MAPK1 and KRAS, in particular, play significant roles in both neurodegeneration and oncogenesis, highlighting their potential as therapeutic targets.

Our findings emphasize the neuroprotective role of estrogen and suggest early hormonal interventions and selective estrogen receptor modulators (SERMs) as potential treatments. Recognizing AD as a metabolic disorder related to impaired insulin signaling opens new therapeutic opportunities. Moreover, plant secondary metabolites show significant potential in modulating these pathways, particularly by targeting MAPKs.

Understanding the shared molecular underpinnings of AD, T2DM, and estrogen dysregulation offers innovative avenues for personalized, multi-targeted therapies. This research marks a significant advancement in the management of AD, T2DM, and related conditions in women, emphasizing the importance of a holistic approach in disease treatment and prevention.