Fig. 5: Shared microglial response drives Aβ clearance after immunization.
From: Microglial mechanisms drive amyloid-β clearance in immunized patients with Alzheimer’s disease
a, Confocal images showing pan-Aβ and IBA1 in FCX brain regions of nAD, AN1792-lim, AN1792-ext and lecanemab-treated patients. b, Percentage of cortical Aβ coverage in cortical and hippocampal regions of AN1792, nAD and the lecanemab case. c, Percentage of cortical Aβ covered by IBA1 in cortical and hippocampal regions of AN1792, nAD and the lecanemab case. d, Clustering of Aβ-rich cortical gray matter spots based on gene expression. e, C2L predictions of scRNA-seq cell types in different Aβ plaque clusters. f, Percentages of Aβ-rich clusters in AN1792, nAD and the lecanemab case. g,h, DEGs in Aβ-rich cluster 6: AN1792 versus nAD (g); lecanemab versus nAD (h). i, Pseudobulked SPP1 expression in Aβ-rich cluster 6. Error bars indicate the s.e.m. P values are from DESeq2. j, Spatial plots showing the abundance of deconvoluted scRNA-seq microglia types; scale bar, 100 μm. k, log2 fold change in predicted abundance of deconvoluted scRNA-seq microglia types in Aβ-rich ST spots versus the rest in AN1792, nAD and the lecanemab case. l,m, DEGs from Mg-2-enriched and Mg-4-enriched Aβ-associated ST spots: AN1792 versus nAD (l); lecanemab versus nAD (m). n, UMAP showing annotated binned nuclei from a high-definition ST assay. o, Spatial plots indicating the distance of nuclei to D54D2-stained Aβ plaques (left) and their annotations (right). p, Percentage of each cell type in the high-definition ST assay at ≥20 µm and <20 µm from Aβ plaques in nAD and the lecanemab case. q, DEGs from myeloid nuclei within <20 µm of Aβ plaques (lecanemab versus nAD). CDR is included as a covariate in the MAST model. r, Spatial plots showing SPP1 expression in binned nuclei around Aβ plaques in the lecanemab HIPP. s,t, Top ten upregulated response DEGs ranked by the average percentile across microglia and Aβ differential expression in AN1792 (s) and lecanemab (t). u, Top ten combined response genes to AN1792 and lecanemab by summing average percentiles of gene ranks. v, Covariate-adjusted Spearman correlation between TREM2 and APOE expression in microglia-enriched gray matter ST spots from AN1792 patients and clinical hallmarks. b,c,i,k, Bar plots display means ± s.e.m. b,c, nAD-AN1792 = 3; iAD-lim = 4; iAD-ext = 4; nAD-LCMB = 3; LCMB = 1. d–f, nAD-AN1792 = 4; iAD-lim = 6; iAD-ext = 4; nAD-LCMB = 3; LCMB = 1. g–i, nAD-AN1792 = 4; iAD = 10; nAD-LCMB = 3; LCMB = 1. k, nAD-AN1792 = 4; iAD-lim = 6; iAD-ext = 6; nAD-LCMB = 3; LCMB = 1. l,m, nAD-AN1792 = 4; iAD-lim = 6; nAD-LCMB = 3; LCMB = 1. n,p–q, nAD = 2; LCMB = 1. v, iAD = 13. g,h,l,m,q, MAST was used to compare expression levels. Covariates included sex, age, CDR and gDNA percentage with sample ID as a random effect (g and l); brain region, CDR and gDNA percentage with brain region and sample ID as a random effect (h and m); CDR (q). i, DESeq2 was used to compare expression levels. Covariates included sex, age, average genes detected, gDNA percentage (AN1792 versus nAD); average genes detected, brain region and gDNA percentage (lecanemab versus nAD). v, Covariates included sex, age, average genes detected and gDNA percentage. g–i,l,m,q,v, P values were FDR adjusted using Benjamini–Hochberg. b,c,k, Statistical tests, guided by Shapiro–Wilk and F tests, included t-tests, Mann–Whitney tests, analysis of variance (ANOVA) with Tukey’s test, Welch’s ANOVA with Dunnett’s T3 test and Kruskal–Wallis with Dunn’s test. AN1792-ext, AN1792 immunized with extensive Aβ clearance; AN1792-lim, AN1792 immunized with limited Aβ clearance; DE, differential expression; ECs, endothelial cells; Mono, monocytes.
