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. 2024 Jul 24;632(8026):858–868. doi: 10.1038/s41586-024-07606-7

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© The Author(s) 2024

Open Access This 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. 5 — a, The concept of CR and CDR scores. Pathology measurements are used to predict global cognitive function, for CR scores, or rate of cognitive decline, for CDR scores. b, The number of significant DEGs in major cell types across nine measures of CR. c–h, Association of astrocyte CR genes with measures of CR (global AD pathology CR score (c), neuritic plaque burden CR score (d), NFT burden CR score (e), tangle density CR score (f), global cognitive (cogn.) function (g) and rate of change of global cognitive function (h)) across six major cell types in the PFC (427 individuals, DEGs were computed using muscat). i, The association between the expression of CR genes in astrocytes across six brain regions and CR to global AD pathology (48 individuals; DEGs were computed using MAST). j–l, RNAscope validation of the differentially expressed astrocyte CR genes PNPLA6 (j), GPCPD1 (k) and CHDH (l) in the PFC of individuals with cognitive impairment (CI) relative to cognitively resilient (CR) individuals. Representative images (top) show AQP4 transcripts (red puncta) and CR gene transcripts (blue puncta). Scale bars, 20 μm (j–l). Quantification (bottom) was performed using unpaired two-tailed Student’s t-tests; P = 0.0249 (j), P = 0.0052 (k), P = 0.0375 (l). Data are mean ± s.e.m. PNPLA6: n = 3 (CI) and n = 4 (CR) individuals; GPCPD1 and CHDH: n = 4 individuals per group. m, Schematic of choline metabolism and polyamine biosynthesis; significant astrocyte CR genes are highlighted.