Synapse loss is an early event in late-onset Alzheimer's disease (LOAD). In this study, we have assessed the capacity of a polygenic risk score (PRS) restricted to synapse-encoding loci to predict LOAD. We used summary statistics from the International Genetics of Alzheimer's Project genome-wide association meta-analysis of 74,046 patients for model construction and tested the "synaptic PRS" in 2 independent data sets of controls and pathologically confirmed LOAD. The mean synaptic PRS was 2.3-fold higher in LOAD than that in controls (p < 0.0001) with a predictive accuracy of 72% in the target data set (n = 439) and 73% in the validation data set (n = 136), a 5%-6% improvement compared with the APOE locus (p < 0.00001). The model comprises 8 variants from 4 previously identified (BIN1, PTK2B, PICALM, APOE) and 2 novel (DLG2, MINK1) LOAD loci involved in glutamate signaling (p = 0.01) or APP catabolism or tau binding (p = 0.005). As the simplest PRS model with good predictive accuracy to predict LOAD, we conclude that synapse-encoding genes are enriched for LOAD risk-modifying loci. The synaptic PRS could be used to identify individuals at risk of LOAD before symptom onset.

中文翻译：

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谷氨酸、Aβ 和 tau 相关通路的遗传变异决定阿尔茨海默病的多基因风险


突触丢失是迟发性阿尔茨海默病 (LOAD) 的早期事件。在这项研究中，我们评估了仅限于突触编码位点的多基因风险评分（PRS）预测 LOAD 的能力。我们使用国际阿尔茨海默病遗传学项目对 74,046 名患者进行全基因组关联荟萃分析的汇总统计数据进行模型构建，并在 2 个独立的对照数据集和病理证实的 LOAD 中测试了“突触 PRS”。 LOAD 中的平均突触 PRS 比对照组高 2.3 倍 (p < 0.0001)，目标数据集 (n = 439) 中的预测准确度为 72%，验证数据集 (n = 136) 中的预测准确度为 73% ，与 APOE 位点相比提高了 5%-6% (p < 0.00001)。该模型包含来自 4 个先前鉴定的 (BIN1、PTK2B、PICALM、APOE) 的 8 个变体和 2 个涉及谷氨酸信号传导 (p = 0.01) 或 APP 分解代谢或 tau 结合 (p = 0.005) 的新负载位点 (DLG2、MINK1)。作为最简单的 PRS 模型，对 LOAD 具有良好的预测准确性，我们得出结论，突触编码基因在 LOAD 风险修改位点上得到了富集。突触 PRS 可用于在症状出现前识别有 LOAD 风险的个体。