<i>BDNF</i> Val66Met predicts cognitive decline in the Wisconsin Registry for Alzheimer's Prevention.

Abstract

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