We further examined the impact of multiple mCAs and found that the associations became stronger with an increasing number of mCAs, particularly among APOE ε4 non-carriers (Fig. 1d and Supplementary Table 4), suggesting a mutational burden effect of mCAs on the risk of AD.10 To formally test this trend, we included the count of mCAs, instead of a binary indicator of mCA presence, in the model, restricted to individuals carrying mCAs. This evidence concerns the gene APOE and Alzheimer disease.