Multimodal normative modeling in Alzheimer’s Disease with introspective variational autoencoders

Normative models in neuroimaging learn patterns of healthy brain distributions to identify deviations in disease subjects, such as those with Alzheimer’s Disease (AD). This study addresses two key limitations of variational autoencoder (VAE)-based normative models: (1) VAEs often struggle to accurately model healthy control distributions, resulting in high reconstruction errors and false positives, and (2) traditional multimodal aggregation methods, like Product-of-Experts (PoE) and Mixture-of-Experts (MoE), can produce uninformative latent representations. To overcome these challenges, we developed a multimodal introspective VAE that enhances normative modeling by achieving more precise representations of healthy anatomy in both the latent space and reconstructions. Additionally, we implemented a Mixture-of-Product-of-Experts (MOPOE) approach, leveraging the strengths of PoE and MoE to efficiently aggregate multimodal information and improve abnormality detection in the latent space. Using multimodal neuroimaging biomarkers from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset, our proposed multimodal introspective VAE demonstrated superior reconstruction of healthy controls and outperformed baseline methods in detecting outliers. Deviations calculated in the aggregated latent space effectively integrated complementary information from multiple modalities, leading to higher likelihood ratios. The model exhibited strong performance in Out-of-Distribution (OOD) detection, achieving clear separation between control and disease cohorts. Additionally, Z-score deviations in specific latent dimensions were mapped to feature-space abnormalities, enabling interpretable identification of brain regions associated with AD pathology.