The <i>BIN1</i> rs744373 Alzheimer's disease risk SNP is associated with faster Aβ‐associated tau accumulation and cognitive decline
Nicolai Franzmeier, Rik Ossenkoppele, Matthias Brendel, Anna Rubinski, Ruben Smith, Atul Kumar, Niklas Mattsson, Olof Strandberg, Marco Duering, Katharina Büerger, Martin Dichgans, Oskar Hansson, Michael Ewers, for the Alzheimer's Disease Neuroimaging Initiative (ADNI)* and the Swedish BioFINDER study
Abstract
INTRODUCTION: The BIN1 rs744373 single nucleotide polymorphism (SNP) is a key genetic risk locus for Alzheimer's disease (AD) associated with tau pathology. Because tau typically accumulates in response to amyloid beta (Aβ), we tested whether BIN1 rs744373 accelerates Aβ-related tau accumulation. METHODS: F-Flortaucipir positron emission tomography (PET), Aβ biomarkers, and longitudinal cognitive assessments. We assessed whether BIN1 rs744373 was associated with faster tau-PET accumulation at a given level of Aβ and whether faster BIN1 rs744373-associated tau-PET accumulation mediated cognitive decline. RESULTS: BIN1 rs744373 risk-allele carriers showed faster global tau-PET accumulation (ADNI/BioFINDER, P < .001/P < .001). We found significant Aβ by rs744373 interactions on global tau-PET change (ADNI: β/standard error [SE] = 0.42/0.14, P = 0.002; BioFINDER: β/SE = -0.35/0.15, P = .021), BIN1 risk-allele carriers showed accelerated tau-PET accumulation at higher Aβ levels. In ADNI, rs744373 effects on cognitive decline were mediated by faster global tau-PET accumulation (β/SE = 0.20/0.07, P = .005). DISCUSSION: BIN1-associated AD risk is potentially driven by accelerated tau accumulation in the face of Aβ.