Investigation of the Potential of PSEN2 Gene Single Nucleotide Polymorphisms in the Development of Alzheimer’s Disease Using In silico Analysis

Alzheimer’s disease (AD), which is the most common form of dementia, is a complex disorder influenced by genetic and environmental factors. This disease is classified into two main types: early-onset and late-onset. In this study, single nucleotide polymorphisms (SNPs) of the PSEN2 gene were extracted from the dbSNP database in NCBI using bioinformatics methods. The effects of these mutations were evaluated individually using the SIFT, PolyPhen, PANTHER, PROVEAN, and I-MUTANT databases. Among the 646 identified mutations, 161 were predicted to be harmful, and 34 were comprehensively examined as high-risk SNPs. The analysis results indicated that four mutations, A415T, N141Y, Y231C, and A407D, had the most detrimental effects on the structure and stability of the PSEN2 protein. Structural modeling showed that these mutations disrupt protein stability and the function of the γ-secretase complex by altering the size, charge, and hydrophobicity of amino acids, potentially leading to increased accumulation of amyloid beta (Aβ) peptides and the progression of Alzheimer’s disease. The findings of this study suggest that these mutations could serve as potential genetic markers for early diagnosis of the disease and therapeutic targets, highlighting their clinical importance in improving genetic screening and the design of novel drugs. Overall, these results could facilitate future experimental research and the development of personalized medical solutions.