AD-Reasoning: Multimodal Guideline-Guided Reasoning for Alzheimer's Disease Diagnosis

Deep learning models for medical image analysis often act as black boxes, seldom aligning with clinical guidelines or explicitly linking decisions to supporting evidence. This is especially critical in Alzheimer's disease (AD), where predictions should be grounded in both anatomical and clinical findings. We present EMAD, a vision-language framework that generates structured AD diagnostic reports in which each claim is explicitly grounded in multimodal evidence. EMAD uses a hierarchical Sentence-Evidence-Anatomy (SEA) grounding mechanism: (i) sentence-to-evidence grounding links generated sentences to clinical evidence phrases, and (ii) evidence-to-anatomy grounding localizes corresponding structures on 3D brain MRI. To reduce dense annotation requirements, we propose GTX-Distill, which transfers grounding behavior from a teacher trained with limited supervision to a student operating on model-generated reports. We further introduce Executable-Rule GRPO, a reinforcement fine-tuning scheme with verifiable rewards that enforces clinical consistency, protocol adherence, and reasoning-diagnosis coherence. On the AD-MultiSense dataset, EMAD achieves state-of-the-art diagnostic accuracy and produces more transparent, anatomically faithful reports than existing methods. We will release code and grounding annotations to support future research in trustworthy medical vision-language models.

Alzheimer's disease (AD) is a growing global health challenge as populations age, and timely, accurate diagnosis is essential to reduce individual and societal burden. However, real-world AD assessment is hampered by incomplete, heterogeneous multimodal data and variability across sites and patient demographics. Although large language models (LLMs) have shown promise in biomedicine, their use in AD has largely been confined to answering narrow, disease-specific questions rather than generating comprehensive diagnostic reports that support clinical decision-making. Here we expand LLM capabilities for clinical decision support by introducing AD-CARE, a modality-agnostic agent that performs guideline-grounded diagnostic assessment from incomplete, heterogeneous inputs without imputing missing modalities. By dynamically orchestrating specialized diagnostic tools and embedding clinical guidelines into LLM-driven reasoning, AD-CARE generates transparent, report-style outputs aligned with real-world clinical workflows. Across six cohorts comprising 10,303 cases, AD-CARE achieved 84.9% diagnostic accuracy, delivering 4.2%-13.7% relative improvements over baseline methods. Despite cohort-level differences, dataset-specific accuracies remain robust (80.4%-98.8%), and the agent consistently outperforms all baselines. AD-CARE reduced performance disparities across racial and age subgroups, decreasing the average dispersion of four metrics by 21%-68% and 28%-51%, respectively. In a controlled reader study, the agent improved neurologist and radiologist accuracy by 6%-11% and more than halved decision time. The framework yielded 2.29%-10.66% absolute gains over eight backbone LLMs and converges their performance. These results show that AD-CARE is a scalable, practically deployable framework that can be integrated into routine clinical workflows for multimodal decision support in AD.

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 ($ρ=0.94$) and OASIS-3 ($ρ=0.96$); 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.