Dementia-Agents: A Multi-Modal Multi-Agent System for Dementia Staging and Phenotyping

Although artificial intelligence (AI) has shown promising performance in several medical tasks, accurate dementia etiology diagnosis with AI remains challenging due to complex overlapping symptoms among diseases. Scaling up the dataset size by combining the cross-center samples may bring a gain in the pursuit of performance, while the inherent data heterogeneity across centers or populations induces the conflict. Conventional multi-task learning paradigms offer a promising framework; however, they fail to consider critical meta information (e.g., site-specific acquisition and modality availability) to combat the heterogeneity. To address this challenge, we propose a Collaborative Meta Knowledge Enhancement (COME) framework for dementia etiology diagnosis, which injects multi-center acquisition semantics, source identifiers, and modality indicators as heterogeneity-aware embeddings into a unified Transformer architecture for scale-up training, enabling explicit modeling of heterogeneity. Besides, a trust-region constrained optimization scheme is designed to regularize the model from spurious correlations during training through a reference model. Across seven independent cohorts, our method achieves state-of-the-art in-domain performance with a mean macro-averaged AUC of 85.62% and a 4.29-point gain over the strongest baseline, while maintaining superior out-of-domain generalization under both cross-center and cross-sequence evaluations. Extensive validation also confirms the alignment between model predictions and established biomarkers (amyloid, tau) and clinical severity, highlighting the potential of COME to enable robust and interpretable dementia diagnostics in real-world settings.

Neurodegenerative diseases such as Alzheimer's disease (AD) require accurate and scalable tools for assessing disease severity, yet current clinical staging remains time-intensive and prone to variability. We propose an attention-enhanced multimodal machine learning framework with ordinal regression for automated and interpretable AD severity staging. The framework integrates T1-weighted MRI with demographic and genetic variables and compares unimodal and multimodal architectures using ordinal and non-ordinal prediction heads. Models were trained and validated using cohort-stratified splits derived from the ADNI, AIBL, and NIFD datasets. A strictly held-out test set was constructed using subjects excluded from all training, validation, preprocessing, and hyperparameter tuning procedures, with subject-level splitting employed throughout to prevent data leakage. Among unimodal approaches, the T1-weighted MRI model achieved slightly higher adjacent-stage accuracy (0.963) and agreement with clinical staging (QWK 0.444) than the tabular model (QWK 0.433). Integrating imaging, demographic, and genetic information improved overall performance. The multimodal non-ordinal baseline achieved the lowest prediction error (MAE 0.340), whereas the ordinal multimodal model achieved the highest adjacent-stage accuracy (0.970) and strongest agreement with clinical staging (QWK 0.549). These findings indicate that ordinal formulations better capture the ordered structure of the CDR scale and yield predictions more consistent with clinical staging. Explainability analyses using Grad CAM++ and SHAP demonstrated anatomically and clinically plausible model behavior, supporting transparent decision-making. Overall, attention-based multimodal learning with ordinal regression represents a robust, interpretable, and scalable approach for automated AD severity staging and AI-assisted clinical decision support.

Dementia is a major and growing global health burden, with Alzheimer's disease (AD) accounting for most cases. Timely and accurate diagnosis is central to managing this burden and increasingly depends on integrating complementary clinical and imaging information. Multimodal deep learning can combine these modalities for AD diagnosis, but how its explanations behave across modalities, fusion strategies, and cohorts remains unclear. We developed an explainable multimodal framework pairing a 3D CNN encoder for T1-weighted MRI with a feedforward network for harmonized clinical and demographic data, comparing varied model setups on three-way and pairwise diagnostic tasks using 6,479 internal records from the ADNI and 1,703 independent records from the OASIS-3. On ADNI, the tabular-only model achieved the highest three-class AUC-ROC of 0.879 and best discriminated cognitively normal (CN) versus mild cognitive impairment (MCI; 0.903), while cross-attention performed best for MCI versus AD (0.861); CN versus AD was highly discriminative overall. On OASIS-3, the vision-only model performed best (three-class AUC-ROC 0.910); CN versus MCI remained difficult, and no fusion strategy consistently outperformed single modalities across tasks and cohorts. SHAP and Integrated Gradients identified the MMSE as the dominant tabular feature in both cohorts, with global feature rankings agreeing strongly in ADNI ($\rho=0.94$) and OASIS-3 ($\rho=0.96$); CAM-based explanations, however, changed with model configuration and cohort. These findings show that multimodal performance and explanations are task, modality, fusion, and cohort-dependent: a dominant cognitive signal persisted across cohorts, but feature contributions and CAM explanations did not, underscoring the need to evaluate explainability under cohort shift rather than as a stable, intrinsic property.