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

Alzheimers Dement. 2022 Jan;18(1):103-115. doi: 10.1002/alz.12371. Epub 2021 Jun 1.


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.

Keywords: Alzheimer's disease; BIN1; amyloid; tau.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Aged
  • Alzheimer Disease / genetics*
  • Amyloid beta-Peptides* / cerebrospinal fluid
  • Amyloid beta-Peptides* / metabolism
  • Biomarkers / cerebrospinal fluid
  • Brain / metabolism
  • Cognitive Dysfunction / metabolism*
  • Female
  • Humans
  • Male
  • Nuclear Proteins / genetics*
  • Polymorphism, Single Nucleotide*
  • Positron-Emission Tomography
  • Tumor Suppressor Proteins / genetics*
  • tau Proteins / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Amyloid beta-Peptides
  • BIN1 protein, human
  • Biomarkers
  • Nuclear Proteins
  • Tumor Suppressor Proteins
  • tau Proteins