Abstract
Abstract Background Dysfunctional dopamine signaling and disruptions in neurotrophic support are potential exacerbators of Alzheimer’s disease (AD) pathophysiology. A single nucleotide polymorphism (SNP) in the dopamine transporter gene (rs6347 in DAT1/SLC6A3) is associated with greater ventricular expansion and lower scores on the Mini Mental State Exam (MMSE; Roussotte et al., 2015). A polymorphism in the brain derived neurotrophic factor gene (Val66Met in BDNF) is related to greater hippocampal atrophy and more severe episodic memory decline for amyloid positive Met carriers (Lim et al., 2013). However, it is unclear whether and how these polymorphisms directly relate to AD pathology. Method We tested a moderated mediation model (Fig. 1) involving both BDNF and DAT1 polymorphisms in a sample of cognitively normal older adults (n = 321) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). This mediation involved DAT1 (independent variable), b‐amyloid (Ab; mediator), and tau pathology (dependent variable) with BDNF as a moderator. Ab and tau were measured both cross‐sectionally and longitudinally with positron emission tomography (PET) tracers [18F]Florbetapir/[18F]Florbetaben and [18F]Flortaucipir, respectively. Result A significant moderated mediation demonstrated that DAT1 and BDNF interacted to predict cross‐sectional Ab‐PET (p = .02) and tau‐PET (p = .04), such that carriers of both DAT1 C and BDNF Met alleles demonstrated greater pathology (Fig. 2), consistent with previous research associating these variants with AD symptoms. Longitudinal analyses replicated these cross‐sectional results, with DAT1 C and BDNF Met carriers exhibiting greater accumulation of tau pathology (p = .0002) and marginally increased Ab accumulation (p = .07). Conclusion Our analyses revealed novel interaction effects between genetic polymorphisms in the DAT1 and BDNF genes. These results suggest that carrying DAT1 CC and BDNF Met results in higher Ab, which then contributes to higher tau pathology. While our analyses do not demonstrate causality, these findings are consistent with current hypotheses of AD in which Ab drives increases in tau pathology (Karran et al., 2011).
