Interpretable deep survival analysis of Alzheimer's disease via metabolic genetic variants

Alzheimer's disease (AD) is a progressive neurodegenerative disease. Traditional models for estimating AD onset cannot capture nonlinear interactions (epistasis) among the numerous genetic variables that contribute to AD risk.

We developed a feedforward neural network (FFN)-Weibull survival model to predict AD onset using large-scale single-nucleotide polymorphism (SNP) data. We integrated an XAI technique, Shapley additive explanations (SHAP), to address the black-box nature of deep learning, interpret model predictions, and quantify the contribution of each genetic factor to AD.

The FFN model achieved a mean concordance index of 0.647, demonstrating an approximately 3.6% improvement over the traditional linear baseline (0.625). The FFN-SHAP model validated established findings, identifying APOE E4 as a primary AD risk factor. APOE E2 strongly protected against AD. Metabolic-disorder-related SNPs had conflicting effects, suggesting gene-environment interactions influence AD onset.

By effectively bypassing the combinatorial explosion of interaction terms, the predictive power of an FFN combined with XAI provides a robust methodological tool for identifying the genetic basis of complex diseases, even in cohorts with limited sample sizes. Our model generated novel testable hypotheses regarding the intricate roles of gene-gene and gene-environment interactions in AD pathogenesis.