Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
Neurobiol Aging. 2022 Oct;118:66-76. doi: 10.1016/j.neurobiolaging.2022.06.011. Epub 2022 Jul 1.
Apolipoprotein E4 (APOE-ε4), the strongest common genetic risk factor for Alzheimer's disease (AD), contributes to worse cognition in older adults. However, many APOE-ε4 carriers remain cognitively normal throughout life, suggesting that neuroprotective factors may be present in these individuals. In this study, we leverage whole-blood RNA sequencing (RNAseq) from 324 older adults to identify genetic modifiers of APOE-ε4 effects on cognition. Expression of RNASE6 interacted with APOE-ε4 status (p = 4.35 × 10) whereby higher RNASE6 expression was associated with worse memory at baseline among APOE-ε4 carriers. This interaction was replicated using RNAseq data from the prefrontal cortex in an independent dataset (N = 535; p = 0.002), suggesting the peripheral effect of RNASE6 is also present in brain tissue. RNASE6 encodes an antimicrobial peptide involved in innate immune response and has been previously observed in a gene co-expression network module with other AD-related inflammatory genes, including TREM2 and MS4A. Together, these data implicate neuroinflammation in cognitive decline, and suggest that innate immune signaling may be detectable in blood and confer differential susceptibility to AD depending on APOE-ε4.
载脂蛋白 E4（APOE-ε4）是阿尔茨海默病（AD）最强的常见遗传风险因素，它会导致老年人认知能力下降。然而，许多 APOE-ε4 携带者在整个生命周期中仍保持认知正常，这表明这些个体中可能存在神经保护因素。在这项研究中，我们利用来自 324 名老年人的全血 RNA 测序（RNAseq）数据，确定了 APOE-ε4 对认知影响的遗传修饰因子。RNASE6 的表达与 APOE-ε4 状态相互作用（p=4.35×10），即 APOE-ε4 携带者的 RNASE6 表达水平较高与基线时的记忆能力下降有关。这一相互作用在另一个独立数据集的前额叶皮层的 RNAseq 数据中得到了复制（N=535;p=0.002），这表明 RNASE6 的外周效应也存在于脑组织中。RNASE6 编码一种参与先天免疫反应的抗菌肽，以前曾在与 AD 相关的炎症基因的基因共表达网络模块中与其他基因（包括 TREM2 和 MS4A）一起观察到。这些数据表明神经炎症与认知能力下降有关，并表明先天免疫信号可能在血液中可检测到，并根据 APOE-ε4 导致对 AD 的不同易感性。
