The BIN1 rs744373 Alzheimer's disease risk SNP is associated with faster Aβ-associated tau accumulation and cognitive decline

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 (A beta), we tested whether BIN1 rs744373 accelerates A beta-related tau accumulation. Methods We included two samples (Alzheimer's Disease Neuroimaging Initiative [ADNI], n = 153; Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably [BioFINDER], n = 63) with longitudinal F-18-Flortaucipir positron emission tomography (PET), A beta biomarkers, and longitudinal cognitive assessments. We assessed whether BIN1 rs744373 was associated with faster tau-PET accumulation at a given level of A beta 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 P < .001). We found significant A beta by rs744373 interactions on global tau-PET change (ADNI: beta/standard error [SE] = 0.42/0.14, P = 0.002; BioFINDER: beta/SE = -0.35/0.15, P = .021), BIN1 risk-allele carriers showed accelerated tau-PET accumulation at higher A beta levels. In ADNI, rs744373 effects on cognitive decline were mediated by faster global tau-PET accumulation (beta/SE = 0.20/0.07, P = .005). Discussion BIN1-associated AD risk is potentially driven by accelerated tau accumulation in the face of A beta.