Division of Mental Health, Atlanta VA Medical Center, Decatur, GA, 30033, USA.
Department of Psychiatry, Emory University School of Medicine, Atlanta, GA, 30322, USA.
Nat Commun. 2019 Apr 8;10(1):1619. doi: 10.1038/s41467-019-09613-z.
In advanced age, some individuals maintain a stable cognitive trajectory while others experience a rapid decline. Such variation in cognitive trajectory is only partially explained by traditional neurodegenerative pathologies. Hence, to identify new processes underlying variation in cognitive trajectory, we perform an unbiased proteome-wide association study of cognitive trajectory in a discovery (n = 104) and replication cohort (n = 39) of initially cognitively unimpaired, longitudinally assessed older-adult brain donors. We find 579 proteins associated with cognitive trajectory after meta-analysis. Notably, we present evidence for increased neuronal mitochondrial activities in cognitive stability regardless of the burden of traditional neuropathologies. Furthermore, we provide additional evidence for increased synaptic abundance and decreased inflammation and apoptosis in cognitive stability. Importantly, we nominate proteins associated with cognitive trajectory, particularly the 38 proteins that act independently of neuropathologies and are also hub proteins of protein co-expression networks, as promising targets for future mechanistic studies of cognitive trajectory.
在老年时期，一些人保持稳定的认知轨迹，而另一些人则经历快速下降。这种认知轨迹的变化仅部分可以用传统的神经退行性病理学来解释。因此，为了确定认知轨迹变化背后的新过程，我们对最初认知正常、长期评估的老年脑捐赠者的发现队列（n=104）和复制队列（n=39）进行了认知轨迹的无偏蛋白质组全关联研究。我们在荟萃分析后发现了 579 种与认知轨迹相关的蛋白质。值得注意的是，我们提供了证据表明，无论传统神经病理学的负担如何，认知稳定与神经元线粒体活性的增加有关。此外，我们还提供了更多证据表明认知稳定与突触丰度增加、炎症和细胞凋亡减少有关。重要的是，我们提名与认知轨迹相关的蛋白质，特别是那些与神经病理学无关且是蛋白质共表达网络的枢纽蛋白的 38 种蛋白质，作为未来认知轨迹的机制研究的有前途的靶点。
