Gender-Specific Next-Generation Sequencing Reveals First Allelic Variation Patterns in Dementia Risk Among...

Alzheimer's disease (AD) and related dementias exhibit significant gender disparities in prevalence and progression, yet the genetic underpinnings of these differences remain incompletely understood. We aimed to observe gender-specific allelic variation patterns in key dementia susceptibility genes among the Bangladeshi population.

The Community Awareness and Research on Early Dementia (CARED) study is a case-control study that recruited age- and gender-adjusted AD patients and healthy controls aged ≥18 years between 2022 and 2024. We conducted a next-generation sequencing (NGS) analysis of 112 individuals (57 males and 55 females), focusing on key genes associated with dementia susceptibility. Chi-square tests were used to assess gender-specific allele frequency differences for each variant. While Bonferroni-corrected thresholds are noted for reference, nominal P-values are reported due to the study's exploratory design and limited sample size.

The NGS analysis of dementia-associated variants found distinct genotype distribution patterns for Apolipoprotein E (APOE) (rs429358, rs7412, and rs405509), Brain-Derived Neurotrophic Factor (BDNF) (rs6265), and Catechol-O-methyltransferase (COMT) (rs4680) in males and females. We observed a higher minor allele frequency (MAF) of APOE rs429358 in females than males (23.7% vs 15.8%), while APOE rs405509 showed a stronger effect in males, with a significantly higher homozygous MAF (17.5% vs 5.5%, P = 0.05). The BDNF variant rs6265 also showed a greater prevalence in males, with a higher proportion of homozygous carriers (10.7% vs 3.8%) than in females. Linkage disequilibrium (LD) analysis revealed a strong association between APOE rs429358 and rs7412 (r² =0.85), with a rapid decay in LD beyond 10 kb (mean r² =0.15) in the APOE region.

We identified APOE rs405509 and BDNF rs6265 as potential genetic variants associated with gender-specific susceptibility to dementia among Bangladeshis. Additionally, APOE variants rs429358 and rs7412 exhibited strong linkage disequilibrium, with rapid decay from the APOE locus, indicating a higher rate of genetic mixing in this population. Given the exploratory nature of this study, large-scale validation is warranted to confirm these findings.