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

Brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE) are key regulators of neuronal function and cognitive health. Genetic variations in these genes, particularly nonsynonymous single-nucleotide polymorphisms (nsSNPs), have been linked to Alzheimer's disease (AD). This study employs a computational approach to predict the potential functional impacts of nsSNPs in BDNF and APOE to explore their contributions to AD pathogenesis.

A total of 3590 BDNF and 27,830 APOE SNPs were retrieved from the dbSNP database. Following quality filtering of coding region localization and minor allele frequency (≥ 0.001), 33 BDNF nsSNPs and 95 APOE nsSNPs underwent systematic analysis. Pathogenicity was assessed using SIFT and PolyPhen-2 algorithms, with functional impact evaluated via CADD scoring. Protein stability effects were predicted using MUpro and I-Mutant tools, and posttranslational modifications were analyzed via a GPS prediction system. Secondary structure alterations were assessed using GOR4, and three-dimensional structural models were generated through SWISS-MODEL with Ramachandran plot validation.

Three variants demonstrated concordant pathogenic predictions: rs1048218 (BDNF Q75H), rs7412 (APOE R176C), and rs769455 (APOE R163C). Protein stability analysis of these variants revealed consistent destabilization for rs1048218 (ΔΔG: -1.001 to -2.08 kcal/mol) and rs7412 (ΔΔG: -0.859 to -0.07 kcal/mol), whereas rs769455 showed conflicting predictions between algorithms. Posttranslational modification sites remained conserved across all the variants. Secondary structure analysis demonstrated minimal α-helix reduction (0.31%-0.81%) with compensatory random coil increases. Three-dimensional modeling revealed preserved overall protein folds despite localized structural perturbations, with acceptable model quality metrics (MolProbity scores ≤ 1.39, Ramachandran favored regions >91%).

In silico analysis suggested that certain nsSNPs in BDNF and APOE may negatively affect protein function and stability, despite preserved structural and posttranslational features. These computational predictions need further experimental validation to better understand their roles in AD pathogenesis.