BIN1 基因 rs744373 阿尔茨海默病风险 SNP 与 Aβ 相关的 tau 积累和认知能力下降加速有关。

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

机构信息

Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany.

Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden.

出版信息

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

DOI:10.1002/alz.12371

PMID:34060233

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 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.

摘要

简介

BIN1 的 rs744373 单核苷酸多态性（SNP）是与 tau 病理学相关的阿尔茨海默病（AD）的关键遗传风险位点。因为 tau 通常会在淀粉样蛋白β（Aβ）的作用下积累，所以我们测试了 BIN1 rs744373 是否会加速 Aβ 相关的 tau 积累。

方法

我们纳入了两个具有纵向 F-Flortaucipir 正电子发射断层扫描（PET）、Aβ 生物标志物和纵向认知评估的样本（阿尔茨海默病神经影像学倡议 [ADNI]，n=153；生物标志物识别神经退行性疾病早期和可靠 [BioFINDER]，n=63）。我们评估了 BIN1 rs744373 是否与给定 Aβ 水平下更快的 tau-PET 积累相关，以及更快的 BIN1 rs744373 相关 tau-PET 积累是否介导认知下降。

结果

BIN1 rs744373 风险等位基因携带者表现出更快的全局 tau-PET 积累（ADNI/BioFINDER，P<0.001/P<0.001）。我们发现全局 tau-PET 变化存在显著的 Aβ 与 rs744373 的相互作用（ADNI：β/标准误差 [SE] = 0.42/0.14，P=0.002；BioFINDER：β/SE = -0.35/0.15，P=0.021），在更高的 Aβ 水平下，BIN1 风险等位基因携带者表现出更快的 tau-PET 积累。在 ADNI 中，rs744373 对认知下降的影响是通过更快的全局 tau-PET 积累介导的（β/SE = 0.20/0.07，P=0.005）。