Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois.
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois.
JAMA Psychiatry. 2020 Nov 1;77(11):1172-1180. doi: 10.1001/jamapsychiatry.2020.1807.
Identifying genes and proteins for cognitive resilience (ie, targets that may be associated with slowing or preventing cognitive decline regardless of the presence, number, or combination of common neuropathologic conditions) provides a complementary approach to developing novel therapeutics for the treatment and prevention of Alzheimer disease and related dementias.
To identify proteins associated with cognitive resilience via a proteome-wide association study of the human dorsolateral prefrontal cortex.
DESIGN, SETTING, AND PARTICIPANTS: This study used data from 391 community-dwelling older persons who participated in the Religious Orders Study and the Rush Memory and Aging Project. The Religious Orders Study began enrollment January 1, 1994, and the Rush Memory and Aging Project began enrollment September 1, 1997, and data were collected and analyzed through October 23, 2019.
Participants had undergone annual detailed clinical examinations, postmortem evaluations, and tandem mass tag proteomics analyses.
The outcome of cognitive resilience was defined as a longitudinal change in cognition over time after controlling for common age-related neuropathologic indices, including Alzheimer disease, Lewy bodies, transactive response DNA-binding protein 43, hippocampal sclerosis, infarcts, and vessel diseases. More than 8000 high abundance proteins were quantified from frozen dorsolateral prefrontal cortex tissue using tandem mass tag and liquid chromatography-mass spectrometry.
There were 391 participants (273 women); their mean (SD) age was 79.7 (6.7) years at baseline and 89.2 (6.5) years at death. Eight cortical proteins were identified in association with cognitive resilience: a higher level of NRN1 (estimate, 0.140; SE, 0.024; P = 7.35 × 10-9), ACTN4 (estimate, 0.321; SE, 0.065; P = 9.94 × 10-7), EPHX4 (estimate, 0.198; SE, 0.042; P = 2.13 × 10-6), RPH3A (estimate, 0.148; SE, 0.031; P = 2.58 × 10-6), SGTB (estimate, 0.211; SE, 0.045; P = 3.28 × 10-6), CPLX1 (estimate, 0.136; SE, 0.029; P = 4.06 × 10-6), and SH3GL1 (estimate, 0.179; SE, 0.039; P = 4.21 × 10-6) and a lower level of UBA1 (estimate, -0.366; SE, 0.076; P = 1.43 × 10-6) were associated with greater resilience.
These protein signals may represent novel targets for the maintenance of cognition in old age.
识别认知弹性的基因和蛋白质（即，可能与减缓或预防认知能力下降有关的目标，而与常见神经病理学状况的存在、数量或组合无关）为开发治疗和预防阿尔茨海默病和相关痴呆症的新型疗法提供了一种补充方法。
通过对人类背外侧前额叶皮层的蛋白质组全关联研究，确定与认知弹性相关的蛋白质。
设计、地点和参与者：本研究使用了 391 名居住在社区的老年人的数据，他们参加了宗教秩序研究和拉什记忆与衰老项目。宗教秩序研究于 1994 年 1 月 1 日开始招募参与者，拉什记忆与衰老项目于 1997 年 9 月 1 日开始招募参与者，数据收集和分析持续到 2019 年 10 月 23 日。
参与者接受了年度详细的临床检查、死后评估和串联质量标签蛋白质组学分析。
认知弹性的结果定义为在控制常见与年龄相关的神经病理学指数（包括阿尔茨海默病、路易体、转导反应 DNA 结合蛋白 43、海马硬化、梗死和血管疾病）后，随时间推移认知的纵向变化。使用串联质量标签和液相色谱-质谱法从冷冻的背外侧前额叶皮层组织中定量了 8000 多种高丰度蛋白质。
共有 391 名参与者（273 名女性）；他们的平均（标准差）年龄为基线时的 79.7（6.7）岁，死亡时的 89.2（6.5）岁。有 8 种皮质蛋白与认知弹性有关：NRN1 水平较高（估计值为 0.140，SE 为 0.024，P = 7.35×10-9），ACTN4 水平较高（估计值为 0.321，SE 为 0.065，P = 9.94×10-7），EPHX4 水平较高（估计值为 0.198，SE 为 0.042，P = 2.13×10-6），RPH3A 水平较高（估计值为 0.148，SE 为 0.031，P = 2.58×10-6），SGTB 水平较高（估计值为 0.211，SE 为 0.045，P = 3.28×10-6），CPLX1 水平较高（估计值为 0.136，SE 为 0.029，P = 4.06×10-6），SH3GL1 水平较高（估计值为 0.179，SE 为 0.039，P = 4.21×10-6），UBA1 水平较低（估计值为-0.366，SE 为 0.076，P = 1.43×10-6）与更大的弹性有关。
这些蛋白质信号可能代表维持老年人认知能力的新目标。
