Exploring shared molecular pathways and gene signatures in type 2 diabetes mellitus and Alzheimer's disease in a Pakistani cohort

Background Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) a growing concern in low- and middle-income countries, including Pakistan. The relationship between T2DM and AD is complex and concerning, as more older adults with T2DM are experiencing cognitive impairment. Objective The study aimed to investigate the relationship between T2DM and AD in a Pakistani population. Through transcriptomic analysis, this research explored shared molecular mechanisms, genes, and pathways between T2DM and AD. Methods Our main cohort includes 820 participants, including individuals with T2DM, AD, T2DM + AD, and controls, from regional hospitals. Gene expression profiling and Ingenuity Pathway Analysis (IPA) were implemented in a subgroup of 18 participants to identify overlapping gene networks and canonical pathways implicated in both diseases. A TLDA array was used to identify genes associated with Amyloid processing and selected pathways. Results Our findings indicate a significant ( p -value 0.05) overlap in 58 dysregulated genes linked to neuroinflammation, mitochondrial dysfunction, and amyloid processing, suggesting shared pathogenic mechanisms in T2DM and AD. Notable genes, such as CXCL5 and APP , were differentially expressed in both conditions, highlighting inflammation's role in neurodegeneration. CAPNS2 and CAPN1 showed the maximum relative expression differences in the TLDA array, providing potential targets for further investigation. Conclusions The study provides insights into the complex interplay between T2DM and AD, revealing common molecular pathways, including neuroinflammation and mitochondrial dysfunction. Despite the small sample size, our findings underscore the importance of exploring these shared mechanisms, as they could play a potential role in future studies to identify early biomarkers.