BDNF Val66Met influences the mediation of sex differences in VLM scores by plasma BDNF in a cohort enriched with risk for Alzheimer‘s disease

Abstract Background Brain‐derived neurotrophic factor (BDNF)—a key neurotrophin involved in synaptic plasticity, neurogenesis, and neuroprotection—has been shown to mediate sex differences in verbal learning and memory (VLM) ability, but it remains unclear whether this relationship is conditionally dependent upon carriage of the Val66Met polymorphism in the BDNF gene. This study investigates how BDNF Val66Met carriage influences the mediation of sex differences in VLM scores by plasma BDNF levels in a cohort enriched for AD risk. Method Cognitively unimpaired participants in the Wisconsin Registry for Alzheimer’s Prevention (WRAP; n=198, age 63.8±6y, 66% women, 66% family history of AD, 38% apolipoprotein E4 (APOE‐ε4) carriers, 31% BDNF Val66Met carriers) underwent the Rey Auditory Verbal Learning Test (RAVLT). Scores from learning trials 3‐5 and the delayed recall test were aggregated as a VLM performance index. Plasma BDNF levels were measured using a Human BDNF Quantikine Immunoassay (R&D Systems). Striatified mediation analysis and bootstrapping were performed to test the conditional dependence of BDNF mediation on BDNF Val66Met carriage, and model covariates included age, APOE‐ε4 carriage, parental history of AD, education, hippocampal volume, and date difference between VLM and plasma data acquisition. Result Stratified mediation models showed a significant association between sex and VLM scores in BDNF Val66Met carriers [β=‐0.61; p=0.04], but no significant association between sex and BDNF levels [β=0.06; p=0.85]. By comparison, in BDNF Val66Val homozygotes, women had significantly higher BDNF levels [β=‐0.62; p<0.01] and VLM scores [β=‐0.77; p<0.01], and bootstrapping showed BDNF to be a significant partial mediator of the effect of sex on VLM [β=‐0.14; 95% CI: ‐.292, ‐.021]. Conclusion This study indicates that BDNF Val66Met carriage may attenuate the mediating role of plasma BDNF expression on the relationship between sex and VLM scores.