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

Alzheimers Dement. 2021 Jun 1. doi: 10.1002/alz.12371. Epub ahead of print. PMID: 34060233.

Authors/Editors: Franzmeier N, Ossenkoppele R, Brendel M, Rubinski A, Smith R, Kumar A, Mattsson-Carlgren N, Strandberg O, Duering M, Buerger K, Dichgans M, Hansson O, Ewers M; Alzheimer's Disease Neuroimaging Initiative (ADNI)* and the Swedish BioFINDER study.
Publication Date: 2021


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: 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 18 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.

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