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

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.


Statistical parameters
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Software and code
Policy information about availability of computer code Data collection Data used in preparation of this manuscript were obtained from the ADNI database (adni. loni.usc.edu).

Data analysis
All data was analyzed using RStudio statistical software, Version 1.1.414 For manuscripts utilizing custom algorithms or software that are central to the research but not yet described in published literature, software must be made available to editors/reviewers upon request. We strongly encourage code deposition in a community repository (e.g. GitHub). See the Nature Research guidelines for submitting code & software for further information.

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Life sciences study design
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Sample size
We included 89 participants from ADNI phase 3 (ClinicalTrials.gov ID: NCT02854033) in whom 18F-AV1451 tau-PET was obtained. 18F-AV1451 PET was added only in phase 3 of ADNI, and is thus only available in a smaller subset of the large ADNI cohort. The current set of 89 subjects resulted from inclusion criteria of the availability of T1-weighted MRI, 18F-AV45 amyloid-PET, cognitive and GWAS data in addition to 18F-AV1451 tau-PET. All imaging modalities had to be obtained at the same study visit For our main analysis, we tested whether BIN1 rs744373 risk-allele carriage was associated with increased AV1451 tau-PET uptake. To this end, we applied ANCOVAs to test whether presence of the BIN1 rs744373 risk allele had an effect on global or regional (i.e. Braak-stage) AV1451 tau-PET SUVRs, controlling for age, gender, education, diagnosis and ApoE 4 carrier status and grey matter volume of the respective tau ROI. To assess any effects of the BIN1 rs744373 SNP on amyloid, we tested the same models this time using global or regional (i.e. amyloid-stages) AV45 amyloid-PET SUVRs. Lastly, we tested whether BIN1 rs744373 risk allele carriage was associated with higher AV1451 tau-PET uptake independent of amyloid. To this end, we conducted linear regression with global AV1451 tau-PET SUVR as a dependent variable and global AV45 amyloid-PET SUVR and BIN1 rs744373 status as independent variables controlling for age, gender, education, ApoE e4 carrier status and diagnosis.