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. 2022 Dec 20;145(3):303–324. doi: 10.1007/s00401-022-02526-0

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© The Author(s) 2022

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 6 — The cellular and synaptic E/I balance in the hippocampus, TCx, and PCx correlates with cognitive performance. a, b Weighted multivariate analysis showing correlation maps for cognitive assessments of CTRL (n = 8) and AD (n = 12) individuals with cellular and synaptic excitatory and inhibitory markers and their ratio from the hippocampus, TCx and PCx. Individuals were scored with the Cognitive Abilities Screening Instrument calibrated using item response theory (CASI-IRT), memory, executive function (Ex. Func), language and visuospatial performance (Visual Sp.). See the cognitive scores section for more information about the use of weight in the analyses. The hippocampus, TCx and PCx showed cellular (cE/I) and transcriptional synaptic E/I (tE/I) ratios correlated with the memory performance of the individuals (p values from Pearson’s correlations). c, d Pearson’s correlation matrix showing cognitive assessments of 86 individuals (56 nondemented, 30 demented AD type) and RNA-seq data of synaptic excitatory (DLG4) and inhibitory (GPHN) markers and their ratio. Hippocampus (n = 75 donors), TCx (n = 79 donors) and PCx (n = 74 donors) (not all the donors had data from the three brain regions). In the hippocampus, memory showed a significant correlation with a reduction in inhibitory synaptic markers and a trend with a loss of excitatory synaptic markers. Cortical regions showed that memory loss better correlates with tE/I ratio increases