Fig. 3: Causal mediation analyses and structural equation modeling of cell-type-specific ADPRS and AD endophenotypes.
a DP partially mediates Ast-ADPRS—NP association (n = 1452). b NP mediates most of the Ast-ADPRS—NFT association (n = 1474), and the direct effect of Ast-ADPRS on NFT is not significant. c NP partially mediates Mic-ADPRS—tau association (n = 1474). d NFT partially mediates Mic-ADPRS—cognitive decline association (n = 1392). The model included NP burden as a covariate. All models in a–d are linear models adjusted for age, sex, education (for cognitive decline slope), APOE ε2 count, APOE ε4 count, genotype batch, and first three genotype principal components, and non-parametric bootstrapping (n = 10,000 iterations) were used to derive empiric two-sided p-values and 95% confidence intervals for the average causal mediated effect, average direct effect, and proportion mediated. Also, see Supplementary Table 16 for further details. e Structural equation modeling (SEM) shows a probable causal relationship between cell-type-specific ADPRS and AD endophenotypes. Black solid arrows indicate phenotype-phenotype associations and red solid arrows indicate genotype-phenotype associations. All depicted associations were nominally significant (p < 0.05). Numbers adjacent to each arrow indicate completely standardized solutions (relative strength of the effect). Model fit metrics indicate an excellent model fit. All linear associations in this SEM are adjusted for age, sex, education (for cognitive decline slope), APOE ε2 count, APOE ε4 count, genotype batch, and first three genotype principal components. Created with Biorender.com. CFI comparative fit index, DP diffuse plaque, Nobs number of observations (participants), Nparameter number of model parameters, NP neuritic plaque, n.s. not significant, RMSEA root mean square error of approximation, SRMR standardized root mean square residual, TLI Tucker Lewis Index.
