Department of Neurology, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Yongsan-gu, Seoul, Republic of Korea.
Department of Neurology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Republic of Korea.
Alzheimers Dement. 2024 Jan;20(1):243-252. doi: 10.1002/alz.13406. Epub 2023 Aug 10.
Our previously developed blood-based transcriptional risk scores (TRS) showed associations with diagnosis and neuroimaging biomarkers for Alzheimer's disease (AD). Here, we developed brain-based TRS.
We integrated AD genome-wide association study summary and expression quantitative trait locus data to prioritize target genes using Mendelian randomization. We calculated TRS using brain transcriptome data of two independent cohorts (N = 878) and performed association analysis of TRS with diagnosis, amyloidopathy, tauopathy, and cognition. We compared AD classification performance of TRS with polygenic risk scores (PRS).
Higher TRS values were significantly associated with AD, amyloidopathy, tauopathy, worse cognition, and faster cognitive decline, which were replicated in an independent cohort. The AD classification performance of PRS was increased with the inclusion of TRS up to 16% with the area under the curve value of 0.850.
Our results suggest brain-based TRS improves the AD classification of PRS and may be a potential AD biomarker.
Transcriptional risk score (TRS) is developed using brain RNA-Seq data. Higher TRS values are shown in Alzheimer's disease (AD). TRS improves the AD classification power of PRS up to 16%. TRS is associated with AD pathology presence. TRS is associated with worse cognitive performance and faster cognitive decline.
我们之前开发的基于血液的转录风险评分（TRS）与阿尔茨海默病（AD）的诊断和神经影像学生物标志物相关。在这里，我们开发了基于大脑的 TRS。
我们整合了 AD 的全基因组关联研究摘要和表达数量性状基因座数据，使用孟德尔随机化优先考虑靶基因。我们使用两个独立队列（N=878）的大脑转录组数据计算 TRS，并对 TRS 与诊断、淀粉样变性、tau 病和认知的相关性进行了关联分析。我们比较了 TRS 与多基因风险评分（PRS）的 AD 分类性能。
更高的 TRS 值与 AD、淀粉样变性、tau 病、认知能力下降和认知能力下降速度更快显著相关，在独立队列中得到了验证。PRS 中包含 TRS 可提高 AD 的分类性能，最高可达 16%，曲线下面积值为 0.850。
我们的结果表明，基于大脑的 TRS 提高了 PRS 的 AD 分类能力，可能是一种潜在的 AD 生物标志物。
TRS 是使用大脑 RNA-Seq 数据开发的。TRS 数值较高与阿尔茨海默病（AD）有关。TRS 可将 PRS 的 AD 分类能力提高高达 16%。TRS 与 AD 病理的存在有关。TRS 与较差的认知表现和较快的认知衰退有关。
