Fig. 4 |. Proportions of cell subsets are associated with AD traits in a cohort of 638 individuals.

a, Scheme of the CelMod algorithm. Input: snRNA-seq-derived signatures of cell types and subsets and expression programs, as well as their proportions across individuals. A two-step algorithm estimates cell subset proportions in bulk RNA-seq samples, training on matching samples using a fivefold cross-validation approach (Methods). b, CelMod estimated cell subset proportions (y axis) match snRNA-seq measured proportions (x axis) (n = 24 independent samples; additional subsets and cell types in Extended Data Fig. 6a,b). R, Spearman correlation. c, Spearman correlations of the CelMod estimated proportions and the snRNA-seq measured proportions for each cell subset (n = 24 individuals). d, Validations of CelMod in an independent dataset. Correlations of CelMod estimated proportions and snRNA-seq from a published dataset are shown³. e, Immunohistochemistry in DLPFC sections of 48 individuals (24 healthy, 24 with cognitive decline), stained for markers for neurons (anti-NeuN, top) and reactive astrocytes (anti-GFAP, bottom). Left, representative immunofluorescence images. DAPI, nuclei. Scale bar, 100 μm. Right, Pearson correlation coefficients of CelMod and immunofluorescence-based estimations of proportions (out of the total number of cells) for all neurons and for GFAP⁺ astrocytes (Ast.2, Ast.3). f, Correlations of bulk cortica protein expression levels to CelMod estimates and to bulk RNA-seq in n = 196 individuals³⁰. g–i, Association scores for the CelMod estimated proportions of all cell subsets (cell subtypes, states or topic models) to cognitive decline rate (g, x axis), tangle burden (h, x axis) and β-amyloid burden (i, x axis). Association score = −log(FDR) × sign(β), from multivariable linear regression analysis (Methods; n = 638 independent samples). Positively (purple) or negatively (turquoise) associated subsets are colored when statistically significant (FDR < 0.01). j, Correlation (color scale) of proportions of cell subsets from snRNA-seq to cognitive decline (n = 24 independent samples). Associations to additional AD traits in Extended Data Fig. 6g. k, Correlation (color scale) of protein levels (rows) to rate of cognitive decline, β-amyloid burden and tangle burden measured in n = 400 individuals. **FDR < 0.01. Left bar, direction of association of the CelMod estimated proportion with the traits (purple, positive; turquoise, negative).