Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
J Alzheimers Dis. 2023;94(4):1549-1561. doi: 10.3233/JAD-230434.
Neuroinflammation and the activation of microglial cells are among the earliest events in Alzheimer's disease (AD). However, direct observation of microglia in living people is not currently possible. Here, we indexed the heritable propensity for neuroinflammation with polygenic risk scores (PRS), using results from a recent genome-wide analysis of a validated post-mortem measure of morphological microglial activation.
We sought to determine whether a PRS for microglial activation (PRSmic) could augment the predictive performance of existing AD PRSs for late-life cognitive impairment.
First, PRSmic were calculated and optimized in a calibration cohort (Alzheimer's Disease Neuroimaging Initiative (ADNI), n = 450), with resampling. Second, predictive performance of optimal PRSmic was assessed in two independent, population-based cohorts (total n = 212,237). Finally, we explored associations of PRSmic with a comprehensive set of imaging and fluid AD biomarkers in ADNI.
Our PRSmic showed no significant improvement in predictive power for either AD diagnosis or cognitive performance in either external cohort. Some nominal associations were found in ADNI, but with inconsistent effect directions.
While genetic scores capable of indexing risk for neuroinflammatory processes in aging are highly desirable, more well-powered genome-wide studies of microglial activation are required. Further, biobank-scale studies would benefit from phenotyping of proximal neuroinflammatory processes to improve the PRS development phase.
神经炎症和小胶质细胞的激活是阿尔茨海默病（AD）最早发生的事件之一。然而，目前还无法直接观察到活体中的小胶质细胞。在这里，我们使用最近对经过验证的死后形态学小胶质细胞激活测量进行的全基因组分析的结果，用多基因风险评分 (PRS) 标记神经炎症的遗传易感性。
我们试图确定针对小胶质细胞激活的 PRS（PRSmic）是否可以增强现有 AD PRS 对晚年认知障碍的预测性能。
首先，在一个校准队列（阿尔茨海默病神经影像学倡议 (ADNI)，n = 450）中通过重新采样计算和优化 PRSmic。其次，在两个独立的基于人群的队列（总 n = 212,237）中评估最佳 PRSmic 的预测性能。最后，我们在 ADNI 中探索了 PRSmic 与一套全面的成像和液体 AD 生物标志物之间的关联。
我们的 PRSmic 并未显著提高 AD 诊断或认知表现的预测能力，在两个外部队列中均如此。在 ADNI 中发现了一些名义上的关联，但效应方向不一致。
虽然需要更强大的全基因组研究来研究与衰老过程中的神经炎症过程相关的遗传评分，但生物库规模的研究也需要对近端神经炎症过程进行表型分析，以改善 PRS 开发阶段。
