APOEFormer: A Multimodal AI Model for APOE4 Carrier Status Prediction and Phenotype Characterization in Alzheimer’s Disease

The apolipoprotein E ε4 (APOE4) allele is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), the most common form of dementia. APOE4 carriers exhibit cerebrovascular and metabolic dysfunction, structural brain alterations, and gut microbiome changes decades before the onset of clinical symptoms. Better understanding of the early manifestation of these physiological changes is critical for development of timely AD interventions and risk reduction protocols. Multi-modal datasets encompassing a wide range of APOE ε4 and AD associated biomarkers provide a valuable opportunity to gain insight into the APOE4 phenotype; however, these datasets often present analytical challenges due to small sample sizes and high heterogeneity. Here, we propose a two-stage multimodal AI model (APOEFormer) that integrates blood metabolites, brain vascular and structural MRI, microbiome profiles, and other clinical and demographic data to predict APOE4 allele status. In the first stage, modality-specific encoders are used to generate initial representations of input data modalities, which are aligned in a shared latent space via self-supervised contrastive learning during pretraining. The contrastive learning objective encourages learning of informative and consistent representations across modalities through leveraging cross-modality relationships. In the second stage, the pretrained representations are used as inputs to a multimodal transformer that integrates information across modalities to predict a key AD-risk genetic variant (APOE4). Across 10 repeated experimental runs with different train–validation–test splits, APOEFormer predicts whether an individual carries an APOE4 allele with an average prediction accuracy of 75%, demonstrating robust performance under limited sample sizes. Post hoc perturbation analysis of the predictive model revealed valuable insights into the driving components of the APOE4 phenotype—including key blood biomarkers and brain regions strongly associated with APOE4.