Synaptic disturbances in excitatory to inhibitory (E/I) balance in forebrain circuits are thought to contribute to the progression of Alzheimer’s disease (AD) and dementia, although direct evidence for such imbalance in humans is lacking. We assessed anatomical and electrophysiological synaptic E/I ratios in post-mortem parietal cortex samples from middle-aged individuals with AD (early-onset) or Down syndrome (DS) by fluorescence deconvolution tomography and microtransplantation of synaptic membranes. Both approaches revealed significantly elevated E/I ratios for AD, but not DS, versus controls. Gene expression studies in an independent AD cohort also demonstrated elevated E/I ratios in individuals with AD as compared to controls. These findings provide evidence of a marked pro-excitatory perturbation of synaptic E/I balance in AD parietal cortex, a region within the default mode network that is overly active in the disorder, and support the hypothesis that E/I imbalances disrupt cognition-related shifts in cortical activity which contribute to the intellectual decline in AD.

前脑回路中兴奋性与抑制性 (E/I) 平衡的突触紊乱被认为会导致阿尔茨海默病 (AD) 和痴呆症的进展，尽管缺乏人类这种不平衡的直接证据。我们通过荧光解卷积断层扫描和突触膜微移植，评估了患有 AD（早发型）或唐氏综合症 (DS) 的中年个体死后顶叶皮层样本的解剖学和电生理学突触 E/I 比值。两种方法均显示，与对照组相比，AD 的 E/I 比率显着升高，但 DS 的 E/I 比率没有显着升高。独立 AD 队列中的基因表达研究也表明，与对照组相比，AD 患者的 E/I 比值升高。这些发现提供了 AD 顶叶皮质中突触 E/I 平衡的显着促兴奋性扰动的证据，顶叶皮层是默认模式网络内的一个区域，在该疾病中过度活跃，并支持 E/I 失衡破坏认知相关的假设。皮质活动的变化导致 AD 患者智力下降。