To determine whether transcriptional risk scores (TRSs), a summation of polarized expression levels of functional genes, reflect the risk of Alzheimer disease (AD).

Blood transcriptome data were from Caucasian participants, which included AD, mild cognitive impairment, and cognitively normal controls (CN) in the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 661) and AddNeuroMed (n = 674) cohorts. To calculate TRSs, we selected functional genes that were expressed under the control of the AD risk loci and were identified as being responsible for AD by using Bayesian colocalization and mendelian randomization methods. Regression was used to investigate the association of the TRS with diagnosis (AD vs CN) and MRI biomarkers (entorhinal thickness and hippocampal volume). Regression was also used to evaluate whether expression of each functional gene was associated with AD diagnosis.

The TRS was significantly associated with AD diagnosis, hippocampal volume, and entorhinal cortical thickness in the ADNI. The association of the TRS with AD diagnosis and entorhinal cortical thickness was also replicated in AddNeuroMed. Among functional genes identified to calculate the TRS, CD33 and PILRA were significantly upregulated, and TRAPPC6A was significantly downregulated in patients with AD compared with CN, all of which were identified in the ADNI and replicated in AddNeuroMed.

The blood-based TRS is significantly associated with AD diagnosis and neuroimaging biomarkers. In blood, CD33 and PILRA were known to be associated with uptake of β-amyloid and herpes simplex virus 1 infection, respectively, both of which may play a role in the pathogenesis of AD.

The study is rated Class III because of the case control design and the risk of spectrum bias.

确定转录风险评分 (TRS)（功能基因极化表达水平的总和）是否反映阿尔茨海默病 (AD) 的风险。

血液转录组数据来自白种人参与者，其中包括阿尔茨海默病神经影像计划 (ADNI，n = 661) 和 AddNeuroMed (n = 674) 队列中的 AD、轻度认知障碍和认知正常对照 (CN)。为了计算 TRS，我们选择了在 AD 风险位点控制下表达的功能基因，并通过使用贝叶斯共定位和孟德尔随机化方法确定为与 AD 相关的功能基因。使用回归研究 TRS 与诊断（AD 与 CN）和 MRI 生物标志物（内嗅厚度和海马体积）的关联。回归还用于评估每个功能基因的表达是否与 AD 诊断相关。

TRS 与 AD 诊断、海马体积和 ADNI 内嗅皮质厚度显着相关。 TRS 与 AD 诊断和内嗅皮质厚度的关联也在 AddNeuroMed 中得到了复制。与 CN 相比，在计算 TRS 时确定的功能基因中，AD 患者中CD33和PILRA显着上调， TRAAPPC6A显着下调，所有这些都在 ADNI 中被识别，并在 AddNeuroMed 中复制。

基于血液的 TRS 与 AD 诊断和神经影像生物标志物显着相关。在血液中， CD33和PILRA分别与 β-淀粉样蛋白和单纯疱疹病毒 1 感染的摄取有关，这两者可能在 AD 的发病机制中发挥作用。

由于病例对照设计和谱系偏倚风险，该研究被评为 III 级。