Preservation of dendritic spines is a putative mechanism of protection against cognitive impairment despite development of Alzheimer Disease (AD)-related pathologies. Aging, the chief late-onset AD risk factor, is associated with dendritic spine loss in select brain areas. However, no study to our knowledge has observed this effect in precuneus, an area selectively vulnerable to early accumulation of AD-related pathology. We therefore quantified dendritic spine density in precuneus from 98 subjects without evidence of neurocognitive decline, spanning ages 20–96, and found a significant negative correlation between age and large dendritic spine density. In these same subjects, we conducted liquid chromatography–tandem mass spectrometry of >5000 proteins and identified 203 proteins which statistically mediate the effect of age on large dendritic spine density. Using computational pharmacology, we identified ten drugs which are predicted to target these mediators, informing future studies designed to test their effects on age-related dendritic spine loss and cognitive decline.

尽管发展了阿尔茨海默病 （AD） 相关病症，但保留树突棘是一种推定的防止认知障碍的机制。衰老是迟发性 AD 的主要危险因素，与特定大脑区域的树突状脊柱丢失有关。然而，据我们所知，没有研究在楔前叶观察到这种影响，楔前叶是一个选择性易受 AD 相关病理早期积累影响的区域。因此，我们量化了 98 名没有神经认知能力下降证据的受试者楔前叶的树突棘密度，年龄跨度为 20-96 岁，发现年龄与树突棘密度之间存在显着的负相关。在这些相同的受试者中，我们对 >5000 个蛋白质进行了液相色谱-串联质谱分析，并鉴定了 203 个蛋白质，这些蛋白质在统计学上介导了年龄对树突状棘密度大的影响。使用计算药理学，我们确定了 10 种预计靶向这些介质的药物，为未来的研究提供信息，这些研究旨在测试它们对与年龄相关的树突状脊柱丧失和认知能力下降的影响。