Assessing the Risk of APOE - ϵ 4 on Alzheimer’s Disease Using Bayesian Additive Regression Trees

Alzheimer’s disease (AD) affects about a tenth of the population aged over 65 and nearly half of those over 85, and the number of AD patients continues to grow. Several studies have shown that the ϵ 4 variant of the apolipoprotein E ( A P O E ) gene is potentially associated with an increased risk of AD. In this study, we aimed to investigate the causal effect of A P O E - ϵ 4 on Alzheimer’s disease under the potential outcome framework and evaluate the individualized risk of disease onset for A P O E - ϵ 4 carriers. A total of 1705 Hispanic individuals from the Washington Heights-Inwood Columbia Aging Project (WHICAP) were included in this study, comprising 453 A P O E - ϵ 4 carriers and 1252 non-carriers. Among them, 265 subjects had developed AD (23.2%). The non-parametric Bayesian additive regression trees (BART) approach was applied to model the individualized causal effects of A P O E - ϵ 4 on disease onset in the presence of right-censored outcomes. The heterogeneous risk of A P O E - ϵ 4 on AD was examined through the individualized posterior survival probability and posterior causal effects. The results showed that, on average, patients carrying A P O E - ϵ 4 were 0.968 years younger at onset than those with non-carrying status, and the disease risk associated with A P O E - ϵ 4 carrying status was 3.9 % higher than that for non-carrying status; however, it should be noted that neither result was statistically significant. The posterior causal effects of A P O E - ϵ 4 for individualized subjects indicate that 14.41% of carriers presented strong evidence of AD risk and approximately 38.65% presented mild evidence, while around 13.71% of non-carriers presented strong evidence of AD risk and 40.89% presented mild evidence. Furthermore, 79.26% of carriers exhibited a posterior probability of disease risk greater than 0.5. In conclusion, no significant causal effect of the A P O E - ϵ 4 gene on AD was observed at the population level, but strong evidence of AD risk was identified in a sub-group of A P O E - ϵ 4 carriers.