Nicolai Franzmeier1, Rik Ossenkoppele2,3, Matthias Brendel4,5, Anna Rubinski1, Ruben Smith2,6, Atul Kumar2, Niklas Mattsson-Carlgren2,6, Olof Strandberg2, Marco Duering1,7,8, Katharina Buerger1,9, Martin Dichgans1,5,9, Oskar Hansson2,10, Michael Ewers1,9. 1. Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany. 2. Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden. 3. Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands. 4. Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany. 5. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. 6. Department of Neurology, Skåne University Hospital, Lund, Sweden. 7. Medical Image Analysis Center (MIAC AG), Basel, Switzerland. 8. Department of Biomedical Engineering, University of Basel, Basel, Switzerland. 9. German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. 10. Memory Clinic, Skåne University Hospital, Lund, Sweden.
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: 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.
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.
Authors: Jolien Schaeverbeke; Emma S Luckett; Silvy Gabel; Mariska Reinartz; Steffi De Meyer; Isabelle Cleynen; Kristel Sleegers; Christine Van Broeckhoven; Guy Bormans; Kim Serdons; Koen Van Laere; Patrick Dupont; Rik Vandenberghe Journal: Alzheimers Dement (N Y) Date: 2022-02-23