Predictive Analysis of Brain-Derived Neurotrophic Factor and Apolipoprotein E SNPs in Alzheimer’s Pathogenesis

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by memory impairment, cognitive decline, and behavioral changes. Genetic susceptibility plays a central role in its development, particularly variants in the apolipoprotein E ( APOE ) gene and neurotrophic regulators such as brain-derived neurotrophic factor ( BDNF ). Nonsynonymous single-nucleotide polymorphisms (nsSNPs) in these genes can alter protein structure and function, potentially contributing to disease progression. This study used computational methods to evaluate the functional and structural consequences of nsSNPs in BDNF and APOE . A total of 3,590 SNPs in BDNF and 27,830 SNPs in APOE were retrieved from the dbSNP database. After filtering for coding-region variants with minor allele frequency ≥ 0.001, 33 BDNF and 95 APOE nsSNPs were selected for further analysis. Pathogenicity predictions were performed using SIFT and PolyPhen-2, while functional impact was assessed using CADD scores. Protein stability changes were analyzed with MUpro and I-Mutant, and potential post-translational modification sites were evaluated using GPS-based prediction. Secondary structure alterations were examined using GOR4, and three-dimensional models were generated through SWISS-MODEL and validated by Ramachandran plot analysis. Several variants, including rs1048218 ( BDNF Q75H), rs7412 ( APOE R176C), and rs769455 ( APOE R163C), showed consistent damaging predictions across multiple tools. Stability analysis indicated marked destabilization for rs1048218 and rs7412, whereas rs769455 showed variable predictions. Structural modeling suggested localized conformational changes without major disruption of the overall fold. These findings suggest that specific nsSNPs in BDNF and APOE may influence protein behavior and contribute to AD pathology. Experimental validation will be necessary to confirm their biological relevance.