BDNF shown to partially mediate greater verbal learning performances in women as compared to men in a cohort enriched with risk for Alzheimer’s disease

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AbstractBackgroundIt is established that the sex‐based prevalence of Alzheimer’s disease (AD) is greater in women, though the mechanisms underlying this difference are not well understood. Furthermore, in cognitively normal adults, women consistently score higher than men in verbal learning ability, a primary domain of cognitive function sensitive to decline from AD progression. The sex‐specific mechanisms of action of brain‐derived neurotrophic factor (BDNF), a growth factor important for memory and long‐term brain health, may explain observed sex‐based differences in cognitive decline. The purpose of this study was to investigate whether sex‐based differences in verbal learning and memory (VLM) are mediated by BDNF expression in a cohort of cognitively normal adults at risk for AD.MethodWisconsin Registry for Alzheimer’s Prevention (WRAP) participants (n=201, age 63.81±6.04, 66.2% women, 65.7% family history of AD, 38% APOE‐ε4 carriers, without known cognitive decline) underwent the Rey Auditory Verbal Learning Test (RAVLT), trials 3‐5 and delayed recall, to assess VLM function. BDNF serum levels were measured using Human BDNF Quatikine Immunoassay DBD00 from R&D Systems. Mediation analysis was performed using the Hayes and Preacher macro for IBM SPSS, adjusting for age, time between variable collection, APOE‐ε4 status, parental AD history, and hippocampal volume.ResultRegression models indicated significantly higher levels of BDNF in women (F(6,191)=2.38, p=0.031, R2 =0.07, β=‐2280.89, t(191)=‐2.52). Women were found to have significantly higher VLM scores (F(6,191)=7.22, p<0.0001, R2=0.18, β=‐0.68, t(191)=‐4.58). Greater BDNF levels indicated higher VLM scores (β<0.00, t(190)=2.49, p=0.014). Controlling for BDNF as a mediator attenuated the effect of sex on VLM, indicating partial mediation from BDNF (β=‐0.61, t(190)=‐4.12, p=0001).ConclusionThis study shows that BDNF level partially mediates the higher scores of women in VLM in a cohort of cognitively normal adults at‐risk for AD, suggesting that sex‐specific differences in BDNF expression may partially explain the differing prevalence of AD between the sexes. However, this difference is likely due to many additional factors, and it is still unknown whether this relationship persists throughout clinical AD. Research is needed on the relationship between BDNF, sex, and VLM in individuals with cognitive impairment, as well as the direct interactions between these factors.