To test for association with the clinical diagnosis of Alzheimer’s disease, we used LeafCutter20 to identify differentially spliced introns by jointly modeling intron clusters using a Dirichlet-multinomial GLM (Online Methods). At a Bonferroni-corrected P < 0.05, we identified a total of 87 intron clusters (corresponding to 84 genes) that displayed altered splicing in relation to Alzheimer’s disease (Supplementary Table 3). Of these, 11 genes are also differentially expressed, suggesting that our splicing analysis is identifying novel associations that had been missed in conventional approaches evaluating gene expression levels alone. For example, the most significant differentially excised intron (chr10: 3147351–3147585) is found in the phosphofructokinase gene (PFKP): the frequency of this splicing event was associated with Alzheimer’s disease (P < 4.9×10−24; β=−0.27) and all pathologic measures tested in this study. Similarly, the next most differentially excised intron (chr14: 21490656–21491400) associated with Alzheimer’s disease is found in the alpha/beta-hydrolase fold protein gene NDRG family member 2 (NDRG2) (P < 5.6 × 10−19; β=−0.058) and is also associated with measures of both amyloid and Tau pathology (Fig. 2c). Differential splicing of both PFKP
