BIN1 rs744373 SNP is associated with increased mean diffusivity in non‐demented elderly

Abstract

AbstractBackgroundThe rs744373 SNP in the bridging integrator‐1 gene (BIN1) is the second most important risk factor of sporadic Alzheimer’s disease (AD) after ApoE genotype. We have recently shown that the BIN1 SNP is associated with higher tau deposition in the brain (Franzmeier et al. Nat Commun 2019). Recent findings indicate that BIN1 protein is highly expressed in the white matter (WM) in the brain. Although WM alterations are common in AD and may contribute to dementia symptoms, it is unclear whether BIN1 risk allele is associated with lower WM integrity. To address this research gap, we tested whether BIN1 rs744373 is associated with WM alterations in non‐demented elderly, independently of amyloid PET.MethodsWe included diffusion tensor imaging (DTI) data, 18‐F AV45 amyloid PET, and AV1451 tau PET from 61 individuals including cognitively normal controls (CN, n=35) and individuals with mild cognitive impaired (MCI, n=26) from ADNI. 14 CN and 15 MCI individuals were BIN1 rs744373 SNP carriers. Global mean diffusivity (MD) and global fractional anisotropy (FA) were mapped within the white matter. In linear voxel‐based regression analyses, we tested the BIN1 rs744373 genotype effect on MD (primary outcome) and FA values, controlled for age, gender, education, diagnosis and global amyloid PET. We further assessed the voxel‐level group differences in MD (BIN1 rs744373 carriers vs. non‐carriers) using TBSS. Tau PET was assessed in projection areas of major fiber tracts.ResultsBIN1 rs744373‐carriage was associated with elevated global white matter MD values (p=0.003, Figure 1), independent of global Aβ PET SUVR, and regional MD predominantly located within the left superior/inferior longitudinal fasciculus, left/right uncinate fasciculus and left inferior fronto‐occipital fasciculus (Figure 2). No significant effect on FA was observed. When stratified by diagnosis, associations between BIN1 rs744373 and elevated global MD were significant in the MCI subgroup (p=0.01). Mediation analyses of the effect of BIN1 on white matter via tau PET in connected areas will be discussed.ConclusionBIN1 rs744373 risk allele is associated with white matter alterations in MCI independent of Aβ, suggesting that BIN1 SNP may enhance the risk of microstructural white matter impairment and thus contribute to dementia symptoms.