The BIN1 rs744373 SNP is associated with increased tau-PET levels and impaired memory

Abstract

The single nucleotide polymorphism (SNP) rs744373 in the bridging integrator-1 gene (BIN1) is a risk factor for Alzheimer's disease (AD). In the brain, BIN1 is involved in endocytosis and sustaining cytoskeleton integrity. Post-mortem and in vitro studies suggest that BIN1-associated AD risk is mediated by increased tau pathology but whether rs744373 is associated with increased tau pathology in vivo is unknown. Here we find in 89 older individuals without dementia, that BIN1 rs744373 risk-allele carriers show higher AV1451 tau-PET across brain regions corresponding to Braak stages II-VI. In contrast, the BIN1 rs744373 SNP was not associated with AV45 amyloid-PET uptake. Furthermore, the rs744373 risk-allele was associated with worse memory performance, mediated by increased global tau levels. Together, our findings suggest that the BIN1 rs744373 SNP is associated with increased tau but not beta-amyloid pathology, suggesting that alterations in BIN1 may contribute to memory deficits via increased tau pathology.

Fig. 1

Staging systems for tau- and amyloid-PET. Spatial mapping of Braak- (a) and amyloid stage-specific ROIs (b) that were used to determine regional AV1451 tau- and AV45 amyloid-PET uptake within the sample of n = 89 subjects

Fig. 2

Effects of BIN1 rs744373 on tau- and amyloid-PET uptake. a Boxplots showing the differences in global or regional AV1451 tau-PET SUVRs between BIN1 rs744373 risk allele (n = 40, yellow) vs. normal-allele carriers (n = 49, blue). P-values are based on ANCOVA models controlled for age, gender, education, diagnosis, memory performance (i.e., ADNI-MEM) and gray matter volume of the respective ROI. b Differences in global or regional AV45 amyloid-PET uptake between BIN1 rs744373 risk allele (n = 40, yellow) vs. normal-allele carriers (n = 49, blue). Boxplots are displayed as median (center line) ±interquartile range (box boundaries) with whiskers including observations falling within the 1.5 interquartile range. P-values are again derived from ANCOVA models controlled for age, gender, education, diagnosis, ApoE ε4 carrier status, and gray matter volume of the respective ROI. *p < 0.05 (uncorrected); ‘ = significant after Bonferroni correction (p < 0.0071)

Fig. 3

BIN1 rs744373 effects on tau across the amyloid spectrum. Boxplot showing the association between BIN1 rs744373 (risk-allele n = 40, yellow; normal-allele n = 49, blue) and global AV1451 tau-PET uptake across amyloid quartiles. The statistical main effects presented in the upper left corner of the graph are derived from linear regression, with the BIN1 rs7443733 SNP and global AV45 amyloid-PET SUVR as predictors, controlling for age, gender, diagnosis, and ApoE ε4 status. Cohens d effects sizes displayed in the plot were derived for each quartile. Note, that no interaction between BIN1 rs744373 and global AV45 amyloid-PET uptake was found, suggesting that the effects of BIN1 rs744373 on tau are similar between high- and low-amyloid groups. Boxplots are displayed as median (center line) ±interquartile range (box boundaries) with whiskers including observations falling within the 1.5 interquartile range

Fig. 4

Spatial patterns of tau-PET and BIN1 mRNA expression. Spatial mapping of median BIN1 mRNA expression (i.e., log₂) derived from the Allen Brain Atlas and group-median AV1451 tau-PET SUVR (derived from n = 89 subjects), either for all ROIs (upper panel) or restricted to regions falling above the 75^th percentile of either BIN1 mRNA expression or group-median AV1451 tau-PET uptake (lower panel). Color scales represent SUVR scores for AV1451 tau-PET and log₂ mRNA expression for BIN1 mRNA

Fig. 5

Association between tau-PET and BIN1 mRNA expression. Scatterplot showing the positive association between ROI-based BIN1 mRNA expression obtained from the Allen Brain Atlas and group-median AV1451 tau-PET uptake (Number of ROIs = 34; Association illustrated as least-squares regression line ±95% confidence interval). P-values and 95% confidence intervals of r-values are derived from bootstrapped spatial regression with 1000 iterations

Fig. 6

Tau mediates effects of BIN1 rs744373 on memory impairment. Path diagram of the mediation model (assessed on the full sample of n = 89 subjects), showing that associations between BIN1 rs744373 risk-allele carriage and worse memory are mediated via global AV1451 tau-PET uptake. Path-weights are displayed as beta values with standard errors in brackets. All paths are controlled for age, gender, education, diagnosis, global AV45 amyloid-PET uptake, and ApoE ε4 carrier status. Asterisks indicate p-values below 0.05. Significance of the indirect effect was determined using bootstrapping with 10,000 iterations