Alzheimer's Disease Classification

Missing modalities are prevalent in real-world Alzheimer's disease (AD) assessment and pose a significant challenge to multimodal learning, particularly when the distribution of observed modality subsets differs between training and deployment. Such missingness pattern mismatch induces a conditional representation shift across modality subsets. Existing approaches that rely on implicit imputation or modality synthesis often fail to explicitly model modality availability and uncertainty, leading to overconfident dependence on synthesized features, reduced robustness, and miscalibrated uncertainty estimates. To address these limitations, we propose PRA-PoE, an incomplete multimodal learning framework that is equipped with Prototype-anchored Representation Alignment (PRA) and an Uncertainty-aware Product of Experts (UA-PoE) fusion mechanism. First, PRA uses learnable global prototypes and availability-conditioned tokens to encode modality availability, distinguish observed from missing modalities, re-synthesize features for missing modalities, and adaptively refine observed representations to align latent spaces across modality subsets, with the goal of reducing representation shift under varying missingness patterns. Second, UA-PoE models each modality as a Gaussian expert and performs closed-form Product of Experts fusion, where experts with higher uncertainty are automatically down-weighted via lower precision, improving uncertainty reliability. We evaluate PRA-PoE under a clinically realistic protocol by training with naturally missing data and testing on all non-empty modality combinations. PRA-PoE consistently outperforms the state-of-the-art across datasets, achieving a 5.4% relative improvement in average accuracy on ADNI and a 10.9% relative gain in average F1 on OASIS-3 over the strongest baseline across all non-empty modality subsets.

Clinical diagnostic workups typically follow a modality escalation pathway: after initial clinical evaluation, clinicians begin with routine structural imaging (e.g., MRI), selectively add sequences such as FLAIR or T2 to refine the differential, and reserve molecular imaging (e.g., amyloid-PET) for cases that remain uncertain after standard evaluation. Consequently, patients are observed with heterogeneous and often incomplete modality subsets. However, most current AI models assume fixed data modalities as the model inputs. In this paper, we present BrainAnytime, a unified pretraining framework pretrained on 34,899 3D brain scans from five datasets that support brain image analysis under arbitrary modality availability spanning multi-sequence MRI and amyloid-PET. A single model accepts whatever imaging is available, from a lone T1 scan to a full multimodal workup. Pretraining learns structural-molecular correspondences between MRI and PET via cross-modal distillation (RCMD) and prioritizes disease-vulnerable anatomy via atlas-guided curriculum masking (PACM), all within a shared 3D masked autoencoder (Multi-MAE3D). Across four downstream tasks and five clinically motivated modality settings, BrainAnytime largely outperforms modality-specific models, missing-modality baselines, and large-scale brain MRI pretrained foundation models on most modality settings. Notably, it surpasses the strongest missing-modality baselines with relative improvements of 6.2% and 7.0% in average accuracy on CN vs. AD and CN vs. MCI classification, respectively. Code is available at https://github.com/SDH-Lab/BrainAnytime.

Deep learning models in medical imaging typically operate as parametric memory, diagnosing patients by recalling fixed knowledge learned during training. This contrasts sharply with clinical practice, where physicians employ analogical reasoning to diagnose new cases by referencing similar records from past exemplars. While In-Context Learning (ICL) frameworks such as Tabular Prior-Fitted Networks (TabPFN) offer a promising diagnosis-by-reference paradigm, they are designed with tabular-specific inductive priors and rely on non-differentiable preprocessing pipelines, leading to manifold mismatch and gradient fracture when applied to heterogeneous multimodal data. To address these limitations, we propose PromptDx, a novel diagnosis-by-reference framework that leverages a pre-trained TabPFN as an ICL engine while enabling seamless integration with multimodal representations. Our core contribution is a Differentiable Prompt Tuning (DPT) mechanism that aligns a Masked Multimodal Modeling module with the pre-trained ICL engine. By training a lightweight adapter as a differentiable surrogate for the engine's non-differentiable preprocessors, we enable an end-to-end optimization of multimodal prompts within the ICL paradigm. We validate our method on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset using 3D MRI and tabular biomarkers. Experiments demonstrate that our approach outperforms traditional parametric baselines. Notably, our method achieves superior performance using only 1% context samples compared to 30% in standard ICL, demonstrating exceptional manifold condensation ability. We further validate the generalizability of our DPT framework across six tabular datasets with diverse scales. Overall, our method offers a more data-efficient and clinically aligned paradigm for Alzheimer's Disease diagnosis.

Multimodal neuroimaging analysis often involves complex, modality-specific preprocessing workflows that require careful configuration, quality control, and coordination across heterogeneous toolchains. Beyond preprocessing, downstream statistical analysis and disease classification commonly require task-specific code, evaluation protocols, and data-format conventions, creating additional barriers between raw acquisitions and reproducible scientific analysis. We present NeuroAgent, an LLM-driven agentic framework that automates key preprocessing and analysis steps for heterogeneous neuroimaging data, including sMRI, fMRI, dMRI, and PET, and supports interactive downstream analysis through natural-language queries. NeuroAgent employs a hierarchical multi-agent architecture with a feedback-driven Generate-Execute-Validate engine: agents autonomously generate executable preprocessing code, detect and recover from runtime errors, and validate output integrity. We evaluate the system on 1,470 subjects pooled across all ADNI phases (CN=1,000, AD=470), where all subjects have sMRI and tabular data, with subsets also having Tau-PET (n=469), fMRI (n=278), and DTI ($n=620$). Pipeline ablation studies across multiple LLM backends show that capable models reach up to 100% intent-parsing accuracy, with the strongest backend (Qwen3.5-27B) reaching 84.8% end-to-end preprocessing step correctness. Automated recovery limits manual intervention to edge cases where human review is required via the Human-In-The-Loop interface. For Alzheimer's Disease classification using automatically preprocessed multimodal data, our agent ensemble achieves an AUC of 0.9518 with four modalities, outperforming all single-modality baselines. These results show that NeuroAgent can reduce the manual effort required for neuroimaging preprocessing and enable end-to-end automated analysis pipelines for neuroimaging research.

Brain MRI foundation models learn rich representations of anatomy, but interpreting what clinical information they encode remains an open problem. Standard sparse autoencoders (SAEs) suffer from severe feature collapse in deep transformer layers, and in Alzheimer's disease (AD) research, aging confounds nearly every clinical variable, making naive annotation unreliable. We propose GeoSAE, a geometry-guided SAE framework that uses the foundation model's learned manifold structure to prevent feature collapse and annotates each surviving feature via age-deconfounded partial correlations. Applied to ~14k T1-weighted MRI scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Australian Imaging biomarkers and Lifestyle (AIBL) datasets, GeoSAE identifies a compact, fully interpretable feature set that predicts mild cognitive impairment (MCI)-to-AD conversion (AUC 0.746) using only 2% of the embedding dimensions, while comorbidity-annotated features achieve only chance-level performance. The identified features replicate across cohorts without retraining (r=0.97) and localize to neuroanatomically distinct regions consistent with Braak staging. This shows that geometry-guided SAEs can extract interpretable, biomarkers from frozen brain MRI foundation models.

Accurate prediction of conversion from Mild Cognitive Impairment (MCI) to Alzheimers Diseases (AD) is essential for early intervention, however, developing reliable conversion predictive models is difficult to develop due to limited longitudinal data availability We evaluate TabPFN (Tabular Pre-Trained Foundation Network) against traditional machine learning methods for predicting 3 year MCI to AD conversion using the TADPOLE dataset derived from ADNI. Using multimodal biomarker features extracted from demographics, APOE4, MRI volumes, CSF markers, and PET imaging, we conducted an experimental comparison across varying training set sizes (N=50 to 1000) and models including XGBoost, Random Forest, LightGBM, and Logistic Regression. TabPFN achieved one the highest performance (AUC=0.892), outperforming LightGBM (AUC=0.860) and demonstrating advantages in low data settings. At N=50 training samples, TabPFN maintained strong AUC while the traditional machine learning models struggles at small training samples. These findings demonstrate that foundation models are promising for disease prediction in data limited scenarios, such as Alzheimers diseases.

Patients with dementia typically exhibit cognitive impairment, which is routinely assessed using the Mini-Mental State Examination (MMSE). Concurrently, their underlying neurophysiological abnormalities are reflected in Electroencephalography (EEG), providing a basis for joint modeling. However, traditional multi-task approaches suffer from feature entanglement, which leads to inter-task interference when handling heterogeneous objectives.To address this challenge, we propose a task-guided spatiotemporal network (TGSN) with diffusion augmentation for EEG-based dementia diagnosis and MMSE prediction. Specifically, TGSN integrates a multi-band feature fusion module to capture complementary spectral information from EEG. Meanwhile, a pre-trained data augmentation module utilizing a diffusion process is introduced toincrease sample diversity. To model the complex spatiotemporal patterns of EEG, we propose a gated spatiotemporal attention module that captures long-range spatial dependencies and temporal dynamics. Moreover, we design a task-guided query module to achieve task-specific feature extraction, thereby mitigating task interference. The effectiveness of TGSN is evaluated on the XY02 dataset. Experimental results demonstrate that the proposed network outperforms several state-of-the-art methods, achieving classification accuracies of 97.78% for Alzheimer's Disease (AD)/Frontotemporal Dementia (FTD) and 83.93% for AD/FTD/Vascular Cognitive Impairment (VCI), which exceed the best baselines by 16.39% and 8.28%, respectively. In parallel, it reduces the RMSE for MMSE prediction to 1.93 and 2.38, achieving significant error reductions of 1.44 and 1.43 compared to the best baselines. Additionally, validation on the DS004504 dataset demonstrates strong cross-dataset generalization...

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and a major cause of dementia. Structural MRI is widely used to analyze AD-related brain atrophy; however, most deep learning methods rely on computationally expensive 3D convolutional neural networks (CNNs), limiting deployment in resource-constrained settings. This work introduces two main contributions. First, we propose a pipeline that converts T1-weighted MRI into anatomically informed 2D point clouds using Anatomical Priority Sampling (APS), producing ADNI-2DPC, the first neuroanatomically labeled MRI-derived point cloud dataset. Second, we present NeuroAPS-Net, a lightweight geometric deep learning model that incorporates anatomical priors via region-aware feature encoding and ROI token aggregation. Experiments on ADNI-2DPC demonstrate that NeuroAPS-Net achieves competitive classification accuracy while significantly reducing inference latency and GPU memory compared to state-of-the-art point cloud methods. These results highlight the potential of anatomically guided point cloud learning as an efficient and interpretable alternative to voxel-based CNNs for AD classification.

The retina provides a unique, noninvasive window into Alzheimer's disease (AD) and dementia, capturing early structural changes through morphometric features, while systemic and lifestyle risk factors reflect well-established contributors to disease susceptibility long before clinical symptom onset. However, current retinal analysis frameworks typically model imaging and risk factors separately, limiting their ability to capture joint multimodal patterns critical for early risk prediction. Moreover, existing methods rarely incorporate mechanisms to organize or align patients with similar retinal and clinical characteristics, constraining the learning of coherent cross-modal associations. To address these limitations, we introduce REVEAL (REtinal-risk Vision-Language Early Alzheimer's Learning), a framework that aligns color fundus photographs with individualized disease-specific risk profiles for predicting incident AD and dementia, on average 8 years before diagnosis (range: 1-11 years). Because real-world risk factors are structured questionnaire data, we translate them into clinically interpretable narratives compatible with pretrained vision-language models (VLMs). We further propose a group-aware contrastive learning (GACL) strategy that clusters patients with similar retinal morphometry and risk factors as positive pairs, strengthening multimodal alignment. This unified representation learning framework substantially outperforms state-of-the-art retinal imaging models paired with clinical text encoders, as well as general-purpose VLMs, demonstrating the value of jointly modeling retinal biomarkers and clinical risk factors. By providing a generalizable and noninvasive approach for early AD and dementia risk stratification, REVEAL has the potential to enable earlier intervention and improve preventive care at the population level.

Alzheimer's disease (AD) confirmation often relies on positron emission tomography (PET) or cerebrospinal fluid (CSF) analysis, which are costly and invasive. Consequently, structural MRI biomarkers such as cortical thickness (CT) are widely used for non-invasive AD screening. Multiscale structural mapping (MSSM) was recently proposed to integrate gray-white matter contrasts (GWCs) with CT from a single T1-weighted MRI (T1w) scan. Building on this framework, we propose MSSM+, together with surface supervertex mapping (SSVM) and a Supervertex Vision Transformer (SV-ViT). 3D T1w images from individuals with AD and cognitively normal (CN) controls were analyzed. MSSM+ extends MSSM by incorporating sulcal depth and cortical curvature at the vertex level. SSVM partitions the cortical surface into supervertices (surface patches) that effectively represent inter- and intra-regional spatial relationships. SV-ViT is a Vision Transformer architecture operating on these supervertices, enabling anatomically informed learning from surface mesh representations. Compared with MSSM, MSSM+ identified more spatially extensive and statistically significant group differences between AD and CN. In AD vs. CN classification, MSSM+ achieved a 3%p higher area under the precision-recall curve than MSSM. Vendor-specific analyses further demonstrated reduced signal variability and consistently improved classification performance across MR manufacturers relative to CT, GWCs, and MSSM. These findings suggest that MSSM+ combined with SV-ViT is a promising MRI-based imaging marker for AD detection prior to CSF/PET confirmation.

Early and reliable detection of Alzheimer's disease (AD) is crucial for timely clinical intervention and improved patient management. It also supports the evaluation of emerging therapeutic strategies. In this paper, we propose a Low-Rank Mixture of Experts (LoRA-MoE) deep learning framework for Alzheimer's disease diagnosis based on handwriting analysis. Handwriting signals provide a non-invasive and scalable digital biomarker that captures subtle cognitive-motor impairments associated with early AD progression. The proposed architecture allows multiple experts to specialize in different handwriting patterns while sharing a common base network. This design enables efficient learning of general representations while reducing interference between experts. Each expert is equipped with lightweight low-rank adapters. This mechanism significantly reduces the number of trainable parameters compared with standard Mixture of Experts (MoE) models and improves training stability. The proposed framework is evaluated on the Diagnosis AlzheimeR WIth haNdwriting (DARWIN) dataset. Extensive experiments are conducted, including ablation studies on key architectural parameters such as hidden dimension size, number of experts, and LoRA rank. The method is compared with multilayer perceptron (MLP) and conventional MoE architectures. In addition, stacking ensemble strategies (StackMean and StackMax) are investigated to improve robustness and predictive performance. Experimental results show that the LoRA-MoE framework achieves powerful diagnostic performance while activating significantly fewer parameters during inference. These results highlight the potential of the proposed approach as an accurate and computationally efficient solution for handwriting-based Alzheimer's disease screening and digital health applications.

Background: Alzheimer's disease (AD) affects over 55 million people worldwide. Accurate, interpretable detection of normal cognition (NC), mild cognitive impairment (MCI), and AD from routine clinical assessments remains a critical unmet need. Methods: An XGBoost classifier was developed for three-class detection using eight clinical features from the Alzheimer's Disease Neuroimaging Initiative (ADNI): MMSE, CDR Global, CDR Sum of Boxes (CDR-SB), MoCA, FAQ, age, sex, and education. Hyperparameters were optimised using Optuna (50 trials); class imbalance was addressed with SMOTE. Performance was evaluated by macro AUC-ROC with 1,000-iteration bootstrap 95% confidence intervals, macro F1, balanced accuracy, and Cohen's kappa. SHAP values provided feature-level explainability. Results: The dataset comprised 1,641 baseline subjects (608 NC, 767 MCI, 266 AD). On five-fold cross-validation, mean macro AUC was 0.983 (SD 0.007), accuracy 0.944 (SD 0.006), and macro F1 0.929 (SD 0.008). On the held-out test set (n = 247), macro AUC was 0.982 (95% CI: 0.965--0.995), accuracy 0.943, balanced accuracy 0.932, macro F1 0.927, and Cohen's kappa 0.909. SHAP analysis identified CDR Global as the dominant predictor for NC and MCI, while CDR-SB and MMSE together drove AD classification. Conclusion: An explainable machine learning model trained on routine clinical assessments achieves near-perfect three-class Alzheimer's detection. SHAP analysis reveals clinically plausible, class-specific feature importance patterns supporting clinical validity. Future work will extend this framework with speech biomarkers for multimodal detection.

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.

Alzheimer's disease (AD) diagnosis requires integrating neuroimaging with heterogeneous clinical evidence and reasoning under established criteria, yet most multimodal models remain opaque and weakly guideline-aligned. We present AD-Reasoning, a multimodal framework that couples structural MRI with six clinical modalities and a rule-based verifier to generate structured, NIA-AA-consistent diagnoses. AD-Reasoning combines modality-specific encoders, bidirectional cross-attention fusion, and reinforcement fine-tuning with verifiable rewards that enforce output format, guideline evidence coverage, and reasoning--decision consistency. We also release AD-MultiSense, a 10,378-visit multimodal QA dataset with guideline-validated rationales built from ADNI/AIBL. On AD-MultiSense, AD-Reasoning achieves state-of-the-art diagnostic accuracy and produces structured rationales that improve transparency over recent baselines, while providing transparent rationales.

Early detection of Alzheimer's disease from spontaneous speech has emerged as a promising non-invasive screening approach. However, the influence of automatic speech recognition (ASR) quality on downstream clinical language modeling remains insufficiently understood. In this study, we investigate Alzheimer's disease detection using lexical features derived from Whisper ASR transcripts on the ADReSSo 2021 diagnosis dataset. We evaluate interpretable machine-learning models, including Logistic Regression and Linear Support Vector Machines, using TF-IDF text representations under repeated 5x5 stratified cross-validation. Our results demonstrate that transcript quality has a statistically significant impact on classification performance. Models trained on Whisper-small transcripts consistently outperform those using Whisper-base transcripts, achieving balanced accuracy above 0.7850 with Linear SVM. Paired statistical testing confirms that the observed improvements are significant. Importantly, classifier complexity contributes less to performance variation than ASR transcription quality. Feature analysis reveals that cognitively normal speakers produce more semantically precise object- and scene-descriptive language, whereas Alzheimer's speech is characterized by vagueness, discourse markers, and increased hesitation patterns. These findings suggest that high-quality ASR can enable simple, interpretable lexical models to achieve competitive Alzheimer's detection performance without explicit acoustic modeling. The study provides a reproducible benchmark pipeline and highlights ASR selection as a critical modeling decision in clinical speech-based artificial intelligence systems.

Automated Alzheimer's Disease (AD) screening has predominantly followed the inductive paradigm of pattern recognition, which directly maps the input signal to the outcome label. This paradigm sacrifices construct validity of clinical protocol for statistical shortcuts. This paper proposes Agentic Cognitive Profiling (ACP), an agentic framework that realigns automated screening with clinical protocol logic across multiple cognitive domains. Rather than learning opaque mappings from transcripts to labels, the framework decomposes standardized assessments into atomic cognitive tasks and orchestrates specialized LLM agents to extract verifiable scoring primitives. Central to our design is decoupling semantic understanding from measurement by delegating all quantification to deterministic function calling, thereby mitigating hallucination and restoring construct validity. Unlike popular datasets that typically comprise around a hundred participants under a single task, we evaluate on a clinically-annotated corpus of 402 participants across eight structured cognitive tasks spanning multiple cognitive domains. The framework achieves 90.5% score match rate in task examination and 85.3% accuracy in AD prediction, surpassing popular baselines while generating interpretable cognitive profiles grounded in behavioral evidence. This work demonstrates that construct validity and predictive performance need not be traded off, charting a path toward AD screening systems that explain rather than merely predict.

Deep learning has become an important tool for Alzheimer's disease (AD) classification from structural MRI. Many existing studies analyze individual 2D slices extracted from MRI volumes, while clinical neuroimaging practice typically relies on the full three dimensional structure of the brain. From this perspective, volumetric analysis may better capture spatial relationships among brain regions that are relevant to disease progression. Motivated by this idea, this work proposes a multimodal 3D convolutional neural network for AD classification using raw OASIS 1 MRI volumes. The model combines structural T1 information with gray matter, white matter, and cerebrospinal fluid probability maps obtained through FSL FAST segmentation in order to capture complementary neuroanatomical information. The proposed approach is evaluated on the clinically labelled OASIS 1 cohort using 5 fold subject level cross validation, achieving a mean accuracy of 72.34% plus or minus 4.66% and a ROC AUC of 0.7781 plus or minus 0.0365. GradCAM visualizations further indicate that the model focuses on anatomically meaningful regions, including the medial temporal lobe and ventricular areas that are known to be associated with Alzheimer's related structural changes. To better understand how data representation and evaluation strategies may influence reported performance, additional diagnostic experiments were conducted on a slice based version of the dataset under both slice level and subject level protocols. These observations help provide context for the volumetric results. Overall, the proposed multimodal 3D framework establishes a reproducible subject level benchmark and highlights the potential benefits of volumetric MRI analysis for Alzheimer's disease classification.

Accurate diagnosis of Alzheimer's disease (AD) requires handling tabular biomarker data, yet such data are often small and incomplete, where deep learning models frequently fail to outperform classical methods. Pretrained large language models (LLMs) offer few-shot generalization, structured reasoning, and interpretable outputs, providing a powerful paradigm shift for clinical prediction. We propose TAP-GPT Tabular Alzheimer's Prediction GPT, a domain-adapted tabular LLM framework built on TableGPT2 and fine-tuned for few-shot AD classification using tabular prompts rather than plain texts. We evaluate TAP-GPT across four ADNI-derived datasets, including QT-PAD biomarkers and region-level structural MRI, amyloid PET, and tau PET for binary AD classification. Across multimodal and unimodal settings, TAP-GPT improves upon its backbone models and outperforms traditional machine learning baselines in the few-shot setting while remaining competitive with state-of-the-art general-purpose LLMs. We show that feature selection mitigates degradation in high-dimensional inputs and that TAP-GPT maintains stable performance under simulated and real-world missingness without imputation. Additionally, TAP-GPT produces structured, modality-aware reasoning aligned with established AD biology and shows greater stability under self-reflection, supporting its use in iterative multi-agent systems. To our knowledge, this is the first systematic application of a tabular-specialized LLM to multimodal biomarker-based AD prediction, demonstrating that such pretrained models can effectively address structured clinical prediction tasks and laying the foundation for tabular LLM-driven multi-agent clinical decision-support systems. The source code is publicly available on GitHub: https://github.com/sophie-kearney/TAP-GPT.

This dissertation investigates privacy-preserving federated learning for Alzheimer's disease classification using three-dimensional MRI data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Existing methodologies often suffer from unrealistic data partitioning, inadequate privacy guarantees, and insufficient benchmarking, limiting their practical deployment in healthcare. To address these gaps, this research proposes a novel site-aware data partitioning strategy that preserves institutional boundaries, reflecting real-world multi-institutional collaborations and data heterogeneity. Furthermore, an Adaptive Local Differential Privacy (ALDP) mechanism is introduced, dynamically adjusting privacy parameters based on training progression and parameter characteristics, thereby significantly improving the privacy-utility trade-off over traditional fixed-noise approaches. Systematic empirical evaluation across multiple client federations and privacy budgets demonstrated that advanced federated optimisation algorithms, particularly FedProx, could equal or surpass centralised training performance while ensuring rigorous privacy protection. Notably, ALDP achieved up to 80.4% accuracy in a two-client configuration, surpassing fixed-noise Local DP by 5-7 percentage points and demonstrating substantially greater training stability. The comprehensive ablation studies and benchmarking establish quantitative standards for privacy-preserving collaborative medical AI, providing practical guidelines for real-world deployment. This work thereby advances the state-of-the-art in federated learning for medical imaging, establishing both methodological foundations and empirical evidence necessary for future privacy-compliant AI adoption in healthcare.

Longitudinal brain MRI is essential for characterizing the progression of neurological diseases such as Alzheimer's disease assessment. However, current deep-learning tools fragment this process: classifiers reduce a scan to a label, volumetric pipelines produce uninterpreted measurements, and vision-language models (VLMs) may generate fluent but potentially hallucinated conclusions. We present LoV3D, a pipeline for training 3D vision-language models, which reads longitudinal T1-weighted brain MRI, produces a region-level anatomical assessment, conducts longitudinal comparison with the prior scan, and finally outputs a three-class diagnosis (Cognitively Normal, Mild Cognitive Impairment, or Dementia) along with a synthesized diagnostic summary. The stepped pipeline grounds the final diagnosis by enforcing label consistency, longitudinal coherence, and biological plausibility, thereby reducing the risks of hallucinations. The training process introduces a clinically-weighted Verifier that scores candidate outputs automatically against normative references derived from standardized volume metrics, driving Direct Preference Optimization without a single human annotation. On a subject-level held-out ADNI test set (479 scans, 258 subjects), LoV3D achieves 93.7% three-class diagnostic accuracy (+34.8% over the no-grounding baseline), 97.2% on two-class diagnosis accuracy (+4% over the SOTA) and 82.6% region-level anatomical classification accuracy (+33.1% over VLM baselines). Zero-shot transfer yields 95.4% on MIRIAD (100% Dementia recall) and 82.9% three-class accuracy on AIBL, confirming high generalizability across sites, scanners, and populations. Code is available at https://github.com/Anonymous-TEVC/LoV-3D.

Magnetic Resonance Imaging (MRI) provides detailed structural information, while functional MRI (fMRI) captures temporal brain activity. In this work, we present a multimodal deep learning framework that integrates MRI and fMRI for multi-class classification of Alzheimer Disease (AD), Mild Cognitive Impairment, and Normal Cognitive State. Structural features are extracted from MRI using 3D convolutional neural networks, while temporal features are learned from fMRI sequences using recurrent architectures. These representations are fused to enable joint spatial-temporal learning. Experiments were conducted on a small paired MRI-fMRI dataset (29 subjects), both with and without data augmentation. Results show that data augmentation substantially improves classification stability and generalization, particularly for the multimodal 3DCNN-LSTM model. In contrast, augmentation was found to be ineffective for a large-scale single-modality MRI dataset. These findings highlight the importance of dataset size and modality when designing augmentation strategies for neuroimaging-based AD classification.

Alzheimer disease (AD) diagnosis and prognosis increasingly rely on machine learning (ML) models. Although these models provide good results, clinical adoption is limited by the need for technical expertise and the lack of trustworthy and consistent model explanations. SHAP (SHapley Additive exPlanations) is com-monly used to interpret AD models, but existing studies tend to focus on explanations for isolated tasks, providing little evidence about their robustness across disease stages, model architectures, or prediction objectives. This paper proposes a multi-level explainability framework that measures the coherence, stabil-ity and consistency of explanations by integrating: (1) within-model coherence metrics between feature importance and SHAP, (2) SHAP stability across AD boundaries, and (3) SHAP cross-task consistency be-tween diagnosis and prognosis. Using AutoML to optimize classifiers on the NACC dataset, we trained four diagnostic and four prognostic models covering the standard AD progression stages. Stability was then evaluated using correlation metrics, top-k feature overlap, SHAP sign consistency, and domain-level contribution ratios. Results show that cognitive and functional markers dominate SHAP explanations in both diagnosis and prognosis. SHAP-SHAP consistency between diagnostic and prognostic models was high across all classifiers, with 100% sign stability and minimal shifts in explanatory magnitude. Domain-level contributions also remained stable, with only minimal increases in genetic features for prognosis. These results demonstrate that SHAP explanations can be quantitatively vali-dated for robustness and transferability, providing clinicians with more reliable interpretations of ML pre-dictions.

Reliable Alzheimer's disease (AD) diagnosis increasingly relies on multimodal assessments combining structural Magnetic Resonance Imaging (MRI) and Electronic Health Records (EHR). However, deploying these models is bottlenecked by modality missingness, as MRI scans are expensive and frequently unavailable in many patient cohorts. Furthermore, synthesizing de novo 3D anatomical scans from sparse, high-dimensional tabular records is technically challenging and poses severe clinical risks. To address this, we introduce MIRAGE, a novel framework that reframes the missing-MRI problem as an anatomy-guided cross-modal latent distillation task. First, MIRAGE leverages a Biomedical Knowledge Graph (KG) and Graph Attention Networks to map heterogeneous EHR variables into a unified embedding space that can be propagated from cohorts with real MRIs to cohorts without them. To bridge the semantic gap and enforce physical spatial awareness, we employ a frozen pre-trained 3D U-Net decoder strictly as an auxiliary regularization engine. Supported by a novel cohort-aggregated skip feature compensation strategy, this decoder acts as a rigorous structural penalty, forcing 1D latent representations to encode biologically plausible, macro-level pathological semantics. By exclusively utilizing this distilled "diagnostic-surrogate" representation during inference, MIRAGE completely bypasses computationally expensive 3D voxel reconstruction. Experiments demonstrate that our framework successfully bridges the missing-modality gap, improving the AD classification rate by 13% compared to unimodal baselines in cohorts without real MRIs.

Understanding how large-scale functional brain networks reorganize during cognitive decline remains a central challenge in neuroimaging. While recent self-supervised models have shown promise for learning representations from resting-state fMRI, their internal mechanisms are difficult to interpret, limiting mechanistic insight. We propose BrainInterNet, a network-aware self-supervised framework based on masked reconstruction with cross-attention that explicitly models inter-network dependencies in rs-fMRI. By selectively masking predefined functional networks and reconstructing them from remaining context, our approach enables direct quantification of network predictability and interpretable analysis of cross-network interactions. We train BrainInterNet on multi-cohort fMRI data (from the ABCD, HCP Development, HCP Young Adults, and HCP Aging datasets) and evaluate on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, in total comprising 5,582 recordings. Our method reveals systematic alterations in the brain's network interactions under AD, including in the default mode, limbic, and attention networks. In parallel, the learned representations support accurate Alzheimer's-spectrum classification and yield a compact summary marker that tracks disease severity longitudinally. Together, these results demonstrate that network-guided masked modeling with cross-attention provides an interpretable and effective framework for characterizing functional reorganization in neurodegeneration.

The current methods for diagnosing Alzheimer Disease using Magnetic Resonance Imaging (MRI) have significant limitations. Many previous studies used 2D Transformers to analyze individual brain slices independently, potentially losing critical 3D contextual information. Region of interest-based models often focus on only a few brain regions despite Alzheimer's affecting multiple areas. Additionally, most classification models rely on a single test, whereas diagnosing Alzheimer's requires a multifaceted approach integrating diverse data sources for a more accurate assessment. This study introduces a novel methodology called the Multiple Inputs and Mixed Data 3D Vision Transformer (MIMD-3DVT). This method processes consecutive slices together to capture the feature dimensions and spatial information, fuses multiple 3D ROI imaging data inputs, and integrates mixed data from demographic factors, cognitive assessments, and brain imaging. The proposed methodology was experimentally evaluated using a combined dataset that included the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Australian Imaging, Biomarker, and Lifestyle Flagship Study of Ageing (AIBL), and the Open Access Series of Imaging Studies (OASIS). Our MIMD-3DVT, utilizing single or multiple ROIs, achieved an accuracy of 97.14%, outperforming the state-of-the-art methods in distinguishing between Normal Cognition and Alzheimer's Disease.

Alzheimer's disease is a progressive neurodegenerative disorder in which mild cognitive impairment (MCI) precedes dementia. Structural MRI provides biomarkers but requires costly infrastructure, limiting population-scale deployment. Speech offers a non-invasive alternative, yet speech-only classifiers are developed independently of neuroimaging and lack biological grounding for CN-versus-MCI classification. We propose MINT (Multimodal Imaging-to-Speech Knowledge Transfer), a three-stage framework that transfers MRI-derived biomarker structure to speech during training. An MRI teacher defines a compact embedding space for CN-versus-MCI classification, while a residual projection head aligns speech representations to this space using a combined geometric loss. The frozen MRI classifier enables imaging-free inference. On ADNI-4, aligned speech achieves performance comparable to speech baselines, while multimodal fusion improves over MRI alone. Ablations identify dropout regularization and self-supervised pretraining as important design choices. To our knowledge, MINT is the first demonstration of MRI-to-speech knowledge transfer for early Alzheimer's screening without imaging at inference.

Early and accurate detection of Alzheimer's disease (AD) remains a major challenge in medical diagnosis due to its subtle onset and progressive nature. This research introduces an explainable ensemble learning Framework designed to classify individuals as Alzheimer's or Non-Alzheimer's using structured clinical, lifestyle, metabolic, and lifestyle features. The workflow incorporates rigorous preprocessing, advanced feature engineering, SMOTE-Tomek hybrid class balancing, and optimized modeling using five ensemble algorithms-Random Forest, XGBoost, LightGBM, CatBoost, and Extra Trees-alongside a deep artificial neural network. Model selection was performed using stratified validation to prevent leakage, and the best-performing model was evaluated on a fully unseen test set. Ensemble methods achieved superior performance over deep learning, with XGBoost, Random Forest, and Soft Voting showing the strongest accuracy, sensitivity, and F1-score profiles. Explainability techniques, including SHAP and feature importance analysis, highlighted MMSE, Functional Assessment Age, and several engineered interaction features as the most influential determinants. The results demonstrate that the proposed framework provides a reliable and transparent approach to Alzheimer's disease prediction, offering strong potential for clinical decision support applications.

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) alters brain electrophysiology and disrupts multichannel EEG dynamics, making accurate and clinically useful EEG-based diagnosis increasingly important for screening and disease monitoring. However, many existing approaches rely on black-box classifiers and do not explicitly model the latent event timing and cross-channel coordination behind their decisions. To address these limitations, we propose LERD, an end-to-end Bayesian latent event--relational dynamical system that infers latent neural events and their relational structure directly from multichannel EEG without event or interaction annotations. LERD combines a continuous-time event inference module with a stochastic event-generation process to capture flexible temporal patterns, while incorporating an electrophysiology-inspired dynamical prior to guide learning in a principled way. We further provide theoretical analysis that yields a tractable IVP-based KL regularizer and stability guarantees for the inferred relational dynamics. Extensive experiments on synthetic benchmarks and two real-world AD EEG cohorts demonstrate that LERD consistently outperforms strong baselines and yields physiology-aligned rate, timing, and graph summaries that help characterize group-level dynamical differences.

Alzheimer's disease (AD) and Lewy body dementia (LBD) present overlapping clinical features yet require distinct diagnostic strategies. While neuroimaging-based brain network analysis is promising, atlas-based representations may obscure individualized anatomy. Gyral folding-based networks using three-hinge gyri provide a biologically grounded alternative, but inter-individual variability in cortical folding results in inconsistent landmark correspondence and highly irregular network sizes, violating the fixed-topology and node-alignment assumptions of most existing graph learning methods, particularly in clinical datasets where pathological changes further amplify anatomical heterogeneity. We therefore propose a probability-invariant random-walk-based framework that classifies individualized gyral folding networks without explicit node alignment. Cortical similarity networks are built from local morphometric features and represented by distributions of anonymized random walks, with an anatomy-aware encoding that preserves permutation invariance. Experiments on a large clinical cohort of AD and LBD subjects show consistent improvements over existing gyral folding and atlas-based models, demonstrating robustness and potential for dementia diagnosis.