BDNF Val66Met predicts cognitive decline in the Wisconsin Registry for Alzheimer's Prevention

Objective: To examine the influence of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on longitudinal cognitive trajectories in a large, cognitively healthy cohort enriched for Alzheimer disease (AD) risk and to understand whether beta-amyloid (Ab) burden plays a moderating role in this relationship. Methods: One thousand twenty-three adults (baseline age 54.94 +/- 6.41 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention underwent BDNF genotyping and cognitive assessment at up to 5 time points (average follow-up 6.92 +/- 3.22 years). A subset (n = 140) underwent C-11-Pittsburgh compound B (PiB) scanning. Covariate-adjusted mixed-effects regression models were used to elucidate the effect of BDNF on cognitive trajectories in 4 cognitive domains, including verbal learning and memory, speed and flexibility, working memory, and immediate memory. Secondary mixed-effects regression models were conducted to examine whether Ab burden, indexed by composite PiB load, modified any observed BDNF-related cognitive trajectories. Results: Compared to BDNF Val/Val homozygotes, Met carriers showed steeper decline in verbal learning and memory (p = 0.002) and speed and flexibility (p = 0.017). In addition, Ab burden moderated the relationship between BDNF and verbal learning and memory such that Met carriers with greater Ab burden showed even steeper cognitive decline (p = 0.033). Conclusions: In a middle-aged cohort with AD risk, carriage of the BDNF Met allele was associated with steeper decline in episodic memory and executive function. This decline was exacerbated by greater Ab burden. These results suggest that the BDNF Val66Met polymorphism may play an important role in cognitive decline and could be considered as a target for novel AD therapeutics.