Grodstein Francine, Yu Lei, de Jager Philip L, Levey Allan, Seyfried Nicholas T, Bennett David A
Rush Alzheimer's Disease Center, Chicago, IL, 60612, USA.
Department of Internal Medicine, Rush University Medical Center, Chicago, IL, 60612, USA.
Aging Brain. 2022;2. doi: 10.1016/j.nbas.2022.100031. Epub 2022 Feb 7.
Some individuals maintain cognitive health despite neuropathology. Targets impacting "cognitive resilience" may provide interventions for preventing dementia without decreasing neuropathology. Neuroticism represents the tendency to experience negative emotions, and is related to worse cognitive resilience. Exploring proteins associated with cognitive resilience risk factors, such as neuroticism, could yield new protein targets. We used 355 postmortem prefrontal cortex from two cohorts to measure 8356 proteins. We identified (i) proteins associated with both neuroticism and cognitive resilience, and (ii) proteins statistically mediating relations of neuroticism to cognitive resilience. We found two proteins, 40S ribosomal proteinS3 (RPS3) and branched chain keto acid dehydrogenase E1, subunit beta (BCKDHB), ranked in the top 1% of smallest p-values in parallel linear regression models of neuroticism to protein levels, and protein levels to cognitive decline resilience. In mediation models, RPS3 and BCKDHB accounted for 25% (p=0.005) of the relation of neuroticism to cognitive resilience. Our sample size is modest, thus results may be due to chance (p-values did not meet Bonferroni significance) and will require further confirmation; however, investigating biologic mediators of associations of risk factors to cognitive resilience may help discover targets to promote cognitive resilience and reduce dementia.
尽管存在神经病理学改变，但一些个体仍保持认知健康。影响“认知弹性”的靶点可能为预防痴呆症提供干预措施，而不减少神经病理学改变。神经质代表体验负面情绪的倾向，与较差的认知弹性有关。探索与认知弹性风险因素（如神经质）相关的蛋白质，可能会产生新的蛋白质靶点。我们使用了来自两个队列的355份死后前额叶皮质样本，测量了8356种蛋白质。我们确定了（i）与神经质和认知弹性均相关的蛋白质，以及（ii）在统计学上介导神经质与认知弹性关系的蛋白质。我们发现两种蛋白质，40S核糖体蛋白S3（RPS3）和支链酮酸脱氢酶E1β亚基（BCKDHB），在神经质与蛋白质水平、蛋白质水平与认知衰退弹性的平行线性回归模型中，p值最小，排名前1%。在中介模型中，RPS3和BCKDHB占神经质与认知弹性关系的25%（p=0.005）。我们的样本量适中，因此结果可能是偶然的（p值未达到Bonferroni显著性），需要进一步证实；然而，研究风险因素与认知弹性关联的生物学中介因素，可能有助于发现促进认知弹性和减少痴呆症的靶点。
