Alzheimer

Clinical decision making heavily relies on predicting the disease progression trajectory by seeking to understand patient's health status which is characterised by multimodal medical data. AI holds great potential for learning useful representations from multimodal medical data to predict disease progression and aid clinical decision making. However, development of predictive AI models is constrained by missing modalities and incomplete tabular data frequently occurring in medical datasets. In addition, disease labels alone may only provide limited supervisory signals for learning representations from high-dimensional multimodal data. Here, we present MMAP, a novel Multimodal Missing-aware Alignment Pretraining method for learning image-tabular representations from incomplete data. An image encoder is pretrained with efficient sigmoid contrastive learning combined with generative reconstruction. A tabular encoder is built upon a tabular foundation model. A missing token generator enables the two encoders to take incomplete data as input, enabling the model to be robust against missing modalities, either with missing images or missing tabular data. We evaluate the clinical usefulness of the learnt multimodal representations on two challenging longitudinal clinical tasks for Alzheimer's disease: predicting disease stage conversion and predicting amyloid status. The proposed method outperforms strong multimodal and unimodal baselines.

Cortical hypometabolism measured by Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) is a highly sensitive biomarker for dementia diagnosis. However, high costs, radiation exposure, and limited accessibility constrain its clinical utility. While cross-modal synthesis from Magnetic Resonance Imaging (MRI) offers a promising alternative, existing volumetric generation methods do not explicitly account for the highly folded cortical geometry, where disease-related patterns predominantly reside. To address this, we introduce a novel surface-based diffusion bridge framework DB-SUiT for MRI-to-PET translation that operates natively on the cortical manifold. A conditional Spherical U-shaped vision Transformer (SUiT) is specifically designed to model the intricate cross-modal relationships while preserving surface topology. It combines spherical convolutional encoders for multi-scale surface feature extraction with bottleneck Transformers to capture long-range spatial dependencies, while incorporating demographic and subcortical conditions to refine the synthesis. Evaluated on two datasets, including subjects with different dementia types, DB-SUiT demonstrates high-fidelity synthesis that substantially outperforms other baselines. In automated dementia classification, synthesized PET surfaces improve performance over MRI by 14.2% and PET volumes by 11.3%, approaching the performance of real PET surfaces. In a blinded reader study, synthetic PET achieved 85.5% diagnostic accuracy, compared with 75.8% for MRI and 95.2% for real PET. This further demonstrates cross-cohort and cross-pathology generalization, as the model was evaluated without retraining on an external cohort that included a dementia subtype not represented during training. Our code is available at https://github.com/ai-med/DB-SUiT.

Representation learning from medical code sequences in electronic health records and medical claims data has been successful in various clinical applications, such as those regarding disease prediction. However, significant challenges remain in extending this approach to the discovery of scientific hypotheses. One reason is that many existing BERT-based models fail to adequately capture the hierarchical structure of medical codes and the complex interactions between diagnoses and treatments. To address these limitations, we propose a new unified pre-training framework that explicitly integrates hierarchical sub-token aggregation, partial masking, and cross-reference mechanisms. The proposed model consistently outperformed existing methods on both pre-training objectives and downstream clinical event prediction tasks, including the onset of dementia and hospitalization. We also conducted an in silico drug repositioning case study targeting Alzheimer's disease. In the hypothesis generation step, our approach successfully rediscovered known promising drugs in a data-driven manner without relying on such external knowledge sources as the literature. Subsequently, in the hypothesis prioritization step, we introduced a Task-Adaptive Representation Approach to alleviate the over-encoding of historical prescription information within diagnostic vectors, enabling the robust prioritization of generated hypotheses. This study establishes an exploratory screening workflow for hypothesis generation and prioritization based on observational associations. Importantly, this framework is not intended to provide causal evidence, but rather to identify promising candidates for subsequent rigorous causal inference. Overall, this study demonstrates that domain-informed representation learning combined with task-adaptive representation control can enable a practical hypothesis discovery workflow.

Deep networks trained on structural MRI for Alzheimer's disease (AD) staging often reach reasonable accuracy while attending to anatomically irrelevant regions, and multimodal models that add clinical tables frequently rely on variables that were used to assign the diagnostic label in the first place. We study both issues with a deliberately lightweight slice-based encoder (ResNet18 with a one-layer Transformer over slices) on 1,075 baseline T1-weighted scans from ADNI-1. First, we use FastSurfer segmentations as an anatomical reference: YOLOv8 models trained on segmentation-derived labels localize Alzheimer-relevant structures with mAP_50 above 0.96, and a Grad-CAM comparison shows that the image-only classifier frequently attends to the skull, orbits and background. Second, we adapt a CLIP-style image - tabular contrastive framework and organize ADNIMERGE variables along a label-leakage spectrum. Fusion with cognitive scores yields 87.3% three-way accuracy, which we treat as a leakage-driven upper bound rather than an imaging result; fusion with regional volumes yields 73.0%. We observe that the choice of contrastive target changes what the image encoder learns: on MCI vs. CN, the image-only head reaches 52.4% when the encoder is aligned to cognitive scores and 73.8% when aligned to volumes, although no tabular input is used at inference. Third, restricting the input to a per-subject crop of the medial temporal lobe raises image-only three-way accuracy from 58.7% to 65.1%. All results come from single runs on a small balanced test set, and we report confidence intervals and the protocol differences that prevent direct comparison with published numbers.

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.

Speech-based automatic detection of Alzheimer's disease (AD) provides a non-invasive and scalable approach to early cognitive screening. AD affects both lexical-semantic organization and speech production, including atypical pauses and word elongations. However, existing methods have yet to fully integrate these paralinguistic cues with linguistic content. We propose LLM-Anchored Paralinguistic Enrichment (LAPE), which enriches LLM-derived linguistic representations with paralinguistic cues through three coordinated innovations. The first is prosodic event textualization, which enables the LLM to model pauses and elongations jointly with lexical content by encoding them as explicit markers with bounded duration-aware repetition. The second is lexico-prosodic unitization and chunking, which preserves event identity and magnitude in both modalities by pooling only consecutive word units. The third is text-anchored paralinguistic fusion, which integrates local and utterance-level speech features by using NormGate to normalize and dynamically scale them relative to text. We evaluate LAPE on ADReSS and ADReSSo using participant-level cross-validation and leave-one-subject-out evaluation. LAPE achieves state-of-the-art performance across all four primary settings. Code will be released upon acceptance.

Speech-based Alzheimer's disease (AD) detection has recently benefited from multimodal foundation-model representations that integrate complementary acoustic and linguistic information. However, conventional probability averaging over these complementary classifiers is unreliable, because their posterior probabilities exhibit mismatched scales: identical values may reflect different confidence levels across models. We propose a robust rank aggregation framework that aggregates normalized prediction ranks instead of posterior probabilities. Each subject is scored by its percentile within a fixed training-cohort distribution of out-of-fold predictions; since rank ordering is invariant to monotonic transformations, this avoids probability-scale mismatch while preserving classifier confidence ordering. A confidence-gated Random Forest further corrects residual errors using clinically interpretable linguistic features, overriding the rank prediction only when the two disagree and the RF is highly confident, without additional deep model training or explicit posterior-probability calibration. On ADReSS2020 and ADReSSo2021, the method achieves accuracies of 95.83% and 90.14%, respectively, comparing favorably with previously reported results.

Speech-based Alzheimer's disease (AD) detection increasingly relies on speech-enhanced and curated versions of the Pitt Corpus, where speech enhancement, sample selection, and demographic balancing are often treated as beneficial preprocessing steps. However, whether these transformations improve real-world AD detection or instead affect model generalization and prediction behavior remains unclear. In this work, we revisit the role of speech preprocessing and dataset curation across widely used benchmarks for speech-based AD detection. We evaluate the speech quality of different datasets, the cross-dataset generalization of multiple deep learning models under matched and mismatched enhancement settings, and the behavior of several recent large audio-language models (LALMs). Experimental results show that across multiple supervised speech models, speech-enhanced datasets often improve in-domain performance while reducing robustness in cross-domain evaluation. Matched enhancement between training and test data alleviates, but does not eliminate, this degradation. LALMs show a similar sensitivity: enhanced datasets induce stronger class imbalance and prediction shifts than unprocessed data. These results suggest that speech preprocessing and dataset curation can substantially influence downstream AD detection behavior, indicating that ``cleaner'' speech datasets are not necessarily more reliable for real-world AD detection.

Electroencephalography (EEG) is a promising, non-invasive, and cost-effective modality for Alzheimer's disease (AD) detection, but deep learning methods are limited by small and imbalanced clinical datasets. Generative augmentation offers a solution, yet existing approaches rely on inefficient class-specific models or fail to capture complex spatial and temporal brain dynamics. To address this, we propose GraM-Diff, a unified classifier-guided Graph-Mamba diffusion framework for EEG synthesis. It embeds Graph Convolutional Networks within a diffusion U-Net to model inter-electrode connectivity and Bidirectional Mamba state-space blocks for linear-complexity long-range temporal modeling. Latent-space classifier guidance lets a single model generate both healthy and pathological EEG within a shared representation, avoiding fragmented per-cohort pipelines. Across four EEG-based AD benchmarks, synthetic augmentation improves classification, yields superior Context-FID and correlation scores over strong generative baselines, and enhances robustness in data-scarce settings.

Alzheimer's disease is a leading cause of death with no cure. Therefore, early detection is critical to slow progression and preserve quality of life. Diagnosis relies on medical history, cognitive tests, physical exams, and MRI brain scans, making deep learning suitable for Alzheimer's classification. This work proposes a benchmark that evaluates ten different convolutional neural network (CNN) architectures (including ResNet, DenseNet, MobileNet, EfficientNet, and VGG family models) under the same held-out test split protocol. A two-stage transfer learning and full fine-tuning pipeline is introduced to perform training using a class-balanced subset (3,900 images) derived from the OASIS medical imaging dataset, comprising 86,437 single-view MRI brain scans labeled into four classifications of Alzheimer's disease: Non-Demented, Very Mild Dementia, Mild Dementia, and Moderate Dementia. The best results were achieved by VGG16, with a 0.9637 validation accuracy and a 0.9533 test accuracy score. A key finding documented in this work is the difficulty of classifying the transition from Non-Demented to Very Mild Demented stages, observed consistently across all ten architectures.

Alzheimer's disease (AD) progression is a longitudinal process with subtle pathological cues in the early stages. Yet, computational constraints have limited most neuroimaging models to either compromise spatial information or limit the number of longitudinal scans. We aim to overcome this bottleneck and fully leverage high-resolution, variable-length T1w structural MRI (4D sMRI) scan sequences. We introduce Parcel2Progression (P2P), a Longitudinal Transformer Framework which tackles this challenge using an Atlas-guided Parcel Encoder that tokenizes 3D scans into a set of richer anatomically grounded representations. A Longitudinal Transformer then integrates irregular, arbitrary-length longitudinal visits with patient age. This synergy delivers two key advantages: (1) parcel-specific interpretability, and (2) computational tractability for long-term analysis, which scales linearly with the number of scans compared to a naive quadratic 4D ViT cost. P2P outperforms prior works and baselines in both MCI (Mild Cognitive Impairment) to AD conversion prediction and AD vs. CN (Cognitively Normal) classification tasks across ADNI, AIBL, and MIRIAD datasets. Leveraging longitudinal scans boosts performance over single-scan baselines by up to 5% and 7% in balanced accuracy for AD classification and MCI conversion prediction tasks, respectively. Interpretability analysis using parcel saliencies and attention rollouts reveals clinically consistent atrophy patterns in AD and MCI subjects. We also demonstrate the frameworks' reliability in anomaly detection using a synthetic dataset, and test the model's generalizability for other neurodegenerative diseases like Frontotemporal Dementia.

Early diagnosis of Alzheimer's disease (AD) is critical for enabling timely interventions that may slow disease progression and improve patient outcomes. There is a growing need for AD detection methods that are non-invasive and cost-effective, especially in real-world clinical settings with diverse patient populations and recording conditions. Speech-based screening addresses these needs by using natural speech collected without specialized equipment. Recent advances in large language models (LLMs) have improved speech analysis by providing rich linguistic representations and strong generalization. In this study, we propose LSEAD, a speech-based AD detection framework using pretrained open-source LLMs. Speech recordings are automatically transcribed, and text embeddings are extracted using locally deployed LLMs. Principal component analysis (PCA) is applied to reduce dimensionality before classification. Because the framework relies only on speech transcripts and locally deployed models, it supports privacy-preserving AD risk assessment without external data exchange. We evaluate LSEAD on the ADReSS20 and ADReSSo2021 benchmark datasets. Experimental results show that LLM-based embeddings generalize well across datasets and improve AD classification accuracy by up to 5 percent over existing methods, especially for early-stage detection. These results demonstrate that LSEAD provides a practical, secure, and scalable approach for early AD screening.

Changes in spontaneous speech provide an early signal of cognitive dysfunction in Alzheimer's disease (AD) that large language models (LLMs) can detect. However, detection alone cannot establish whether the underlying model representations contribute functionally to behavior. We introduce an activation-guided intervention framework using Qwen3-8B. The framework identifies feed-forward neurons with higher activation rates for AD than control transcripts and modulates their output contributions during generation by scaling the corresponding down-projection weights. This yielded nine edited variants differing in intervention direction, magnitude, and scope. The original and edited models completed the same 12-turn neuropsychological battery, assessed through blinded human ratings and computational linguistic measures. Amplifying AD-associated neurons produced graded impairments in story recall, verbal fluency, working memory, procedural discourse, scene construction, and coreference resolution. Attenuation largely preserved performance and selectively improved several outcomes. Amplification also reduced lexical surprisal, idea density, syntactic complexity, and discourse quantity, broadly paralleling changes reported in human AD speech. These findings show that neurons identified solely from clinical language differences can influence behavior across multiple cognitive domains, providing proof of concept for an AD-related computational phenotype and a controlled framework for experimentally examining links between language and broader cognitive dysfunction.

End-to-end autonomous driving (E2E AD) systems integrate perception, prediction, and planning into a single differentiable architecture. While these models show great promise, their standard training often relies on output-only supervision, which can lead to weak gradients for the hidden layers of increasingly complex models. Recent works have integrated vision-language model (VLM) supervision for latent features to address this, yielding substantial empirical gains, yet leaving the underlying theoretical mechanisms poorly understood. Our investigation into this methodology reveals that the resulting performance gains stem not from VLM reasoning capabilities, as previously assumed, but rather from the latent connections forged between the E2E AD model and ground-truth (GT) data during training. Building on this insight, we propose a probabilistic deep supervision framework that regularizes intermediate latent representations directly from GT data. By treating model latents as reparameterizable distributions, we optimize the architecture via the Evidence Lower Bound (ELBO). Our evaluations conducted on the nuScenes dataset demonstrate that supervising trajectory-related latents with future GT paths consistently improves planning performance. Using identical training data and E2E architectures, our method achieves an 8% reduction in planning L2 error and a 3% decrease in collision rates compared to competitive vectorized baselines, all while incurring negligible computational overhead.

Identifying reliable Alzheimer's disease (AD) markers typically requires manual, labor-intensive transcription and expert analysis, limiting its scale. We introduce an automated pipeline that extracts qualitative knowledge about potential AD progression indicators directly from audio recordings of verbal fluency tests. Our method uses pretrained foundation models to process raw audio and extract clinically relevant variables to construct a Bayesian Network (BN); this BN is used to reason about the AD progression markers and infer their qualitative relationships. Our system successfully recovers known clinical knowledge and identifies novel relationships between linguistic markers.

Functional magnetic resonance imaging (fMRI) is a widely used technique for studying the brain. Recent methods that utilize graph neural networks (GNNs) for analysis of brain functional connectivity have shown great potential for the classification of brain disorders, such as Alzheimer's disease (AD). However, these methods often assume a preset number of functional modules across all subjects, which overlooks inter-subject variability. In addition, the discovered modules are rarely used to directly guide the learned connectivity patterns. Here, to address these issues, we propose a Meta Probabilistic Pooling GNN (MPP-GNN). We frame the model's task as a coupled, bilevel optimization that performs adaptive graph partitioning hierarchically to discover subject-specific modules and then uses the discovered brain modules as an explicit prior to guide edge refinement and representation learning. We validate MPP-GNN on two public datasets for AD classification, achieving the highest AUC in comparison to established baselines for both datasets. Furthermore, our analysis demonstrates that MPP-GNN shows significant alignment with the canonical functional-network organization defined by the Yeo brain atlas and reveals a network-level dedifferentiation pattern for AD.

Accurate identification of Alzheimers disease (AD) using resting-state functional magnetic resonance imaging (rs-fMRI) remains challenging due to the high dimensionality, noise, and complex inter-regional dependencies inherent in functional brain connectivity, which limit the effectiveness of traditional approaches based on handcrafted connectivity features or conventional machine learning models. In this work, we present an attention-based deep learning framework for Alzheimers disease classification that operates directly on rs-fMRI functional connectivity matrices by treating brain regions as tokens and employing a Transformer-inspired self-attention mechanism to model long-range and global functional dependencies across distributed brain networks. The proposed framework learns discriminative functional representations without reliance on manual feature engineering and is evaluated on a longitudinal cohort from the Alzheimers Disease Neuroimaging Initiative (ADNI) comprising cognitively normal and Alzheimers disease subjects with multiple visits. A subject-wise evaluation protocol is adopted to prevent information leakage across visits, and class-weighted optimization is incorporated to address mild class imbalance. Experimental results for binary AD versus cognitively normal classification demonstrate that the proposed attention- based rs-fMRI model achieves an accuracy of 88.95% and a ROC-AUC of 0.90, along with a favorable precision-recall balance, highlighting the effectiveness of self-attention-driven functional connectivity modeling as a robust and interpretable approach for Alzheimers disease detection using resting-state fMRI.

Acoustic biomarkers show promise for detecting Alzheimer's Disease (AD), yet whether the cues driving diagnostic AI align with those salient to human listeners is underexplored across languages and genders, where pathological markers and perceptual strategies differ. We train models to predict clinical AD status (pathology) and human perceptual scores across Mandarin and Greek, male and female speakers. Using SHAP for interpretability and statistical models for validation, we compare feature importance by subgroup. Results reveal a context-dependent divergence: pathological-perceptual alignment is significant for Mandarin and female speakers but disappears for Greek and male speakers, where pathology models did not exceed chance; this is a failure mode that population-specific auditing surfaces. Global Explainable AI (XAI) explanations can mask critical demographic divergences, highlighting the need for population-specific explainability auditing for equitable deployment of clinical speech AI.

Electroencephalography (EEG) is widely used to diagnose neurological conditions, but its analysis usually relies on either predefined spectral features or deep neural networks. Predefined features carry a strong bias, since they fix in advance what counts as informative, while deep neural networks and foundation models are hard to interpret and need large amounts of data and compute. We present bag-of-waves, an interpretable framework that learns a small dictionary of recurring EEG waveform templates, called atoms, using shift-invariant k-means without labels. The continuous EEG is then turned into a sequence of atom tokens, whose counts feed a simple downstream classifier or clustering step. We extend this representation in two ways: we add atom-to-atom transitions, which we call n- grams, to capture temporal structure, and we move from single-channel atoms to regional and cross-channel spatial atoms for the multichannel case. We test the method on three complementary datasets, each probing a different aspect: single-channel mouse genotype clustering with only sixteen animals (the low-data and temporal case), resting-state dementia classification (the spatial case), and the TUEV benchmark, a six-way classification of clinical EEG events (a high-data comparison against strong deep and foundation baselines). Across all three datasets, bag-of-waves achieves performance competitive with state-of-the-art deep and foundation models. Yet, it operates with a fraction of the parameter count and provides full interpretability: because every atom corresponds to an inspectable waveform, the method explicitly recovers known clinical morphologies that a neurophysiologist can directly validate. Its main advantage is that it works in the low-data regime where heavier models are a poor fit.

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.

More than a million people in the UK suffer from frailty or dementia, which severely compromise their ability to travel in urban environments. This paper presents SafeStep, an AI-driven travel system that assists elderly users with their journeys. At the core of SafeStep is a novel travel graph representation, which integrates route planning with predictive modelling. For each stage of a journey, the system (i) generates personalized failure scenarios using a combi-nation of LLMs and the Anticip8 behavioral prediction engine, (ii) proposes targeted interventions, and (iii) estimates the impact of interventions on out-come probabilities. This enables SafeStep to select interventions that maximize the likelihood of the person reaching their destination. SafeStep was evaluated through experiments on travel graph generation and a field study involving 26 real-world journeys. Results showed that combining Anticip8 for failure pre-diction with GPT-based models for intervention evaluation yields the most re-liable performance. User feedback indicated that SafeStep improves confidence and perceived safety during travel, although interface usability needs to be im-proved for the target demographic. In the future, we would like to improve and release SafeStep. The AI system that was developed for SafeStep could be ap-plied in other areas, such as mental health, career coaching and addiction treatment.

Real-time EEG classification on edge devices is bottlenecked by the floating-point arithmetic of conventional neural networks. We investigated Differentiable Logic Gate Networks (Diff-Logic) as a hardware-native alternative that compiles models into pure Boolean circuits executable via bitwise CPU operations. Through rigorous iso-parameter experiments across four EEG datasets spanning two classification tasks, binary dementia detection and 3-class emotion recognition, we compared Diff-Logic against matched-capacity Multi-Layer Perceptron (MLP) and Binarized Neural Network (BNN) baselines at four complexity tiers (50k-500k parameters). On dementia screening, Diff-Logic achieved 80.2% Macro F1, outperforming the MLP baseline by 6.8%. On emotion recognition, the MLP retained a moderate performance advantage but incurred a 2.3$\times$ higher latency and 14$\times$ larger model size when deployed on a power-constrained (7W) Nvidia Jetson Orin Nano CPU (Single-core). Critically, Diff-Logic inference time remained nearly constant across a 10$\times$ increase in model scale, achieving a peak speedup of 2.9$\times$ over MLPs at the largest complexity tier. Our results establish logic-based neural architectures as a practical paradigm for resource-constrained brain-computer interfaces, achieving competitive or superior performance while natively satisfying the latency and memory constraints of portable edge deployment. Code is available on GitHub: https://github.com/Shyamal-Dharia/eeg-difflogic

Background. Predicting conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) is central to trial enrichment and care planning, yet existing models provide no individual-level uncertainty estimates and rarely include transparent leakage audits. We introduce the first application of persistent homology to longitudinal clinical trajectory point clouds for this task, and the first split-conformal individual risk guarantee for any AD-conversion model. Methods. We analysed 741 MCI subjects (240 converters, 32.4%) from ADNI with a uniform 4-year follow-up cap. Five leakage sources were corrected; without them a naive pipeline achieved AUC=0.934, inflated by +0.075. Vietoris-Rips persistent homology and sublevel-set proxies were combined with trajectory slopes and engineered features (76 total) in a stacking ensemble evaluated by 5-fold cross-validation. Results. Cox and Random Survival Forest models with TDA features achieved concordance C=0.799 and C=0.826 versus C=0.753 and C=0.812 without (+0.045 and +0.014). The primary nested AUC is 0.840 (same-fold bound 0.866); external AUC was 0.879 on a zero-overlap ADNI-2/GO/3 cohort. H0 persistence entropy was the top SHAP feature and significantly associated with APOE4 dosage (Spearman r=-0.191, p<0.0001, Bonferroni-corrected). Cross-conformal coverage was 90.4%+-2.2% (target 90%); empirical external coverage 96.9%. Maximum fairness gap in false-negative rate across seven subgroups was 0.092. Conclusions. We propose H0 persistence entropy as a topological biomarker of cognitive decline and demonstrate that a leakage-audited, conformally calibrated pipeline reaches competitive accuracy with individual-level uncertainty quantification not previously available for this task.

Speech recordings used for dementia detection inherently expose speaker identity, raising critical privacy concerns. Existing methods typically address only singular threats and fail to resolve the privacy--utility trade-off. We propose a multi-level framework designed to neutralize two distinct eavesdropping vectors. At the signal level, a Cumulative Signal Attack (CSA) concentrates perturbations in keyword-aligned regions to maximize transcription error (Word Error Rate WER = 1.00) while preserving vital prosodic biomarkers. At the feature level, a Gradient Reversal Layer (GRL) with Mutual Information (MI)-guided noise injection suppresses speaker-discriminative dimensions while retaining dementia-relevant diagnostic structure. Evaluated on the DementiaBank Pitt Corpus, our framework achieves near-chance speaker identification (Equal Error Rate EER = 0.59, F1 = 0.003) while maintaining strong dementia classification performance (F1 = 0.78, AUC = 0.86).

Amyotrophic lateral sclerosis (ALS) is a progressive and heterogeneous neurodegenerative disease in which predicting clinically meaningful milestones, such as assistive device use, remains challenging. We developed a time-to-event, digital-twin-inspired framework that integrates longitudinal ALS Functional Rating Scale-Revised (ALSFRS-R) trajectories with survival modeling to support individualized prediction of functional decline and assistive device utilization. We constructed a harmonized longitudinal dataset by integrating diagnosis records, ALSFRS-R assessments, activities of daily living, and demographic information, followed by preprocessing to ensure data quality, temporal alignment, and cohort consistency. Correlation-based clustering identified coherent functional domains spanning bulbar, upper limb, axial, lower limb, and respiratory systems. Generalized additive mixed models characterized nonlinear, domain-specific functional decline across all domains. In addition, a temporal machine learning model was developed to predict longitudinal functional decline and capture stage-dependent disease progression. Cox proportional hazards modeling further identified lower limb function, particularly walking and stair climbing, as the strongest predictors of earlier wheelchair access. Building on these results, we implemented a digital twin-inspired temporal machine learning-based time-to-event (TTE) model that generates individualized survival curves and dynamically predicts wheelchair-free survival. This framework provides a scalable, interpretable, and clinically actionable approach for linking ALS progression with personalized decision support, with applications in proactive care planning, clinical trial stratification, and precision medicine.

Accurate diagnostic classification and disease-severity prediction for Alzheimer's disease are hampered by the incompleteness and heterogeneity of real-world clinical data. Left unaddressed, these barriers prevent reliable disease modelling and hinder effective clinical evaluation. Conventional imputation strategies introduce systematic bias, distort inter-feature relationships, and yield overconfident predictions, limitations especially consequential in diagnostic settings. Here, we propose NITROGEN, an imputation-free transformer that jointly models within-patient feature dependencies and between-patient relational structure through masked and intersample attention, enabling robust multimodal learning directly from partially observed records. We trained NITROGEN on ADNI (N=7858 scans), and evaluated it on two independent cohorts: OASIS-3 (N=2675 scans) and AIBL (N=1286 scans). Across cohorts and diagnostic and cognitive score prediction tasks, NITROGEN showed robust calibration and uncertainty quantification advantages over tree-based ensemble methods, while maintaining competitive discriminative performance. Cross-cohort and cross-method analyses identified cortical thickness in the temporal pole, age, and APOE genotype as important, though not individually sufficient, features for AD classification. We further introduced a modality-aware uncertainty adjustment that augments predictive uncertainty proportionally to the importance of absent modalities, enabling calibrated confidence when diagnostic information is unavailable. Together, our results show that imputation-free attention learning preserved meaningful discrimination under cohort shift, revealing expected degradation on more distributionally different cohorts, and demonstrate that evaluating models along calibration, interpretability, and cross-cohort reliability, not accuracy alone, is essential for clinical deployment.

It is still hard to find Alzheimer's disease (AD) early, especially when neuroimaging is expensive or tools that depend on language are not available. Spontaneous speech provides a non-invasive signal; however, numerous current methodologies depend on transcripts/ASR or computationally intensive deep models. We offer a simple, audio-only baseline for detecting AD using 176 Cookie Theft recordings from the DementiaBank Pitt corpus (88 AD, 88 controls). WebRTC voice activity detection (VAD) is used to separate speech from non-speech. We take out 99 hand-crafted acoustic-temporal features, including pause and fluency statistics, spectral/prosodic descriptors, and MFCC summaries with Δ and ΔΔ. Evaluation is performed using a stringent speaker-independent GroupShuffleSplit,documenting performance across 30 iterations. A lightweight SVM with an RBF kernel gets an average AUC of 0.674 across runs. For example, a single split has an AUC of 0.742 and an accuracy of 0.657. We also present an exploratory compact-feature analysis utilizing a Top-20 subset ranked by Random Forest importance; since selection is not nested within training splits, these results may be overly optimistic and are not employed for primary conclusions (AUC 0.719). The results indicate that transcript-free spectro-temporal and fluency-related cues can facilitate speaker-independent Alzheimer's disease screening from raw audio, establishing a practical foundation for deployment-oriented research.

Quantifying variability in a target population relative to a reference population is central to many scientific and clinical problems (e.g., diseased vs. healthy). Yet, without paired data and in the presence of heterogeneous target variation, existing methods struggle to separate multiple modes of target-specific variation. We propose \textit{CASL-VAE}, a deep contrastive latent variable model that learns structured latent generative factors from unpaired data. CASL-VAE factorizes variation into continuous common latent factors shared across populations and hierarchical salient latent factors that model target-specific heterogeneity as discrete subtypes and continuous within-subtype variation. Using variational inference, we show how approximate joint likelihood optimization over reference and target domains can be performed using unpaired data, providing a principled basis for paired-sample generation and cross-domain analysis. We validate CASL-VAE on semi-synthetic neuroimaging data, demonstrating improved subtype recovery and paired-sample generation compared to baseline clustering and generative models. We also validate its ability to reveal biologically plausible heterogeneity in Alzheimer's disease.

Social robots offer a promising means of supporting cognitive therapies for dementia care by guiding structured conversation and therapeutic activities. However, little is known about the conversational dynamics that emerge during robot-delivered cognitive stimulation therapy (CST) sessions. This study analysed the interaction patterns from robot-delivered individual CST (iCST) sessions conducted with people living with dementia in home settings. Our Co-STAR (Cognitive Stimulation Therapy by an Autonomous Robot) system was deployed in the homes of eight PwDs for one week, who completed 30-minute sessions. Conversational metrics, including words per turn, speech production rate, response duration, response latency, and self-referential language, were analysed to examine how conversational engagement is shaped by prompt personalisation, interaction phase, and participant characteristics. The findings highlight three key interactional properties of robot-delivered iCST. First, personalised prompts significantly increase response duration, self-referential language, and overall engagement compared to generic prompts. Second, conversational behaviour changes within sessions, with a reduction in the verbal output and autobiographical engagement observed during later interaction phases, which suggests cognitive fatigue. Third, first-session conversational metrics were associated with long-term participation, while living situation influenced conversational engagement patterns. These findings provide empirical insights into the factors that shape conversational engagement in robot-delivered iCST. They inform the design of adaptive conversational robots for dementia therapy.

Alzheimer's disease (AD) is a common neurodegenerative disorder, and early diagnosis is of great significance for delaying disease progression and enabling timely intervention. Mild cognitive impairment (MCI), which represents an intermediate clinical stage between cognitively normal aging and AD. Structural magnetic resonance imaging (sMRI) provides detailed characterization of anatomical structures and plays an important role in AD-related brain analysis. However, existing sMRI-based brain network methods typically rely on a single graph construction strategy, limiting their ability to jointly capture spatial relationships and morphological similarities between brain regions. To address these issues, this paper proposes an sMRI-based multi-view masked graph neural network model (MVMGNN) for AD diagnosis. A joint node-edge masking mechanism is proposed to simultaneously select radiomics feature dimensions and structural connections, reducing redundancy during graph learning. Furthermore, a patient-level cross-view gated fusion mechanism is proposed to integrate multi-view representations. Experimental results on the ADNI dataset demonstrate that MVMGNN outperforms several competing approaches in AD classification. Interpretability analysis further demonstrates that MVMGNN is able to identify key brain regions associated with AD, providing useful insights into discriminative patterns in sMRI-based brain networks.Our implementation is publicly available at https://github.com/chenzhao2023/MVMGNN_AD

In longitudinal Alzheimer's disease (AD) diagnosis support, clinical and imaging information is often collected at irregular visits. Integrating these multimodal observations may improve diagnostic assessment, but naive fusion can degrade performance when MRI is noisy or intermittently unavailable. We propose AT-Attn, a temporal-aware multimodal framework that combines Change-and-Time encoding, time-biased asymmetric cross-attention, and gated fusion to integrate MRI with longitudinal clinical information. We evaluate AT-Attn on an MRI-retained ADNI cohort of 1,520 patients using structural MRI, six cognitive-scale trajectories, and seven static clinical variables under patient-level five-fold cross-validation. The main asymmetric AT-Attn model achieves accuracy 0.719+/-0.024, macro F1 0.721+/-0.023, ROC-AUC 0.873+/-0.013, and PR-AUC 0.783+/-0.018, outperforming unimodal and naive multimodal fusion baselines while remaining competitive with strong tabular baselines. These results suggest that a temporal-aware and constrained fusion strategy can help structural MRI contribute clinically relevant complementary information for patient-level AD diagnosis support.

Cognitive therapies have been shown to enhance the quality of life and well-being of people living with dementia (PwDs). However, their use remains limited due to a shortage of trained professionals and the significant time and training required of informal caregivers. To address this gap, we developed and deployed a social robot capable of autonomously delivering cognitive stimulation therapy (CST) in the home. Nine PwDs participated in a one-week ($7$ days) study that involved daily robot-led sessions. Participants engaged positively with the system, completing nearly half of the scheduled sessions, an adherence rate higher than typically observed in caregiver-led CST. Our findings also highlight the crucial role of family members, who often supported session initiation and occasionally joined the activities, enriching the interactions. This work demonstrates the feasibility and potential of socially assistive robots to deliver in-home cognitive therapy, offering a scalable approach to extend access to dementia care.

Alzheimers disease (AD) is a brain disorder that develops slowly and mainly affects memory, thinking, language, and daily activities. It is one of the most common causes of dementia and creates many difficulties for patients as well as their families. In the early stage, the symptoms are often mild and may look like normal ageing. For this reason, many people are diagnosed late, when the disease has already progressed. At present, there is no complete cure for AD. Still, early detection can help doctors manage the condition better and take suitable steps at the right time. In this study, a machine learning model is proposed to detect the early stages of Alzheimers disease using clinical details, neuropsychological test scores, and neuroimaging-related measures. The data used in this work is collected from the Alzheimers Disease Neuroimaging Initiative (ADNI). As the dataset has missing values, iterative imputation is applied to fill them. The dataset also has class imbalance, which is handled using Borderline SVM-SMOTE. After that, feature selection is carried out using wrapper-based and embedded methods so that only important features are used for training. The selected features are divided into training and testing sets, and feature scaling is applied. A stacking ensemble model is developed using Logistic Regression, Extra Trees, Bagging KNN, and LightGBM as base classifiers. Along with this, an artificial neural network is also trained on the same dataset. The performance of these models is compared using precision, recall, F1-score, and AUC-ROC. This study aims to find the best classifier and also identify important biomarkers that may help in the early diagnosis of Alzheimers disease.

INTRODUCTION: Accurate MRI-based identification of Alzheimer's disease (AD), mild cognitive impairment (MCI), and related dementias remains challenging because disease-related structural changes are often subtle and heterogeneous. We developed NeuroBridge, a clinically guided multi-task MRI framework for neurodegenerative disease diagnosis. METHODS: NeuroBridge integrates large-scale self-supervised MRI pretraining with hippocampal segmentation, hippocampal atrophy classification, and reconstruction objectives, followed by gated fusion fine-tuning. Performance was evaluated across ADNI and OASIS cohorts, including cross-cohort transfer, probability-based analysis, and opportunistic screening. RESULTS: NeuroBridge achieved the highest performance across evaluated classification tasks, reaching 88.17% accuracy for AD versus cognitively normal controls in ADNI and 82.78% in OASIS. The largest gains occurred in MCI-related and mixed-diagnosis settings. The framework demonstrated strong cross-cohort generalization, systematic associations between predicted-class probability and accuracy, and the feasibility of probability-based opportunistic screening. DISCUSSION: Clinically guided multi-task representation learning improves neurodegenerative MRI diagnosis beyond conventional single-task approaches. NeuroBridge provides a robust and scalable framework for dementia assessment and MRI-based opportunistic screening.

Spontaneous speech is a vital non-invasive biomarker for Alzheimer's Disease (AD), yet many systems overlook non-linear structural disruptions and clinical heterogeneity in pathological language. We propose a Multi-View Gated Graph Attention Network that transcribes audio via Automatic Speech Recognition (ASR) to construct semantic, dependency, and co-occurrence graphs, characterizing speech through a "content-structure-flow" framework. Notably, the co-occurrence graph leverages Pointwise Mutual Information (PMI) from a normative corpus to quantify narrative logic and linguistic deviation. To address symptomatic diversity, an adaptive gated fusion mechanism dynamically integrates these views. Evaluated on the ADReSSo dataset, our model achieves 90.00% accuracy. Ablation results confirm that the PMI-based graph and heterogeneity-aware gating are essential for robust classification across diverse clinical populations. Our source code is publicly available at https://github.com/opeacc/AD.

Accurately predicting the temporal evolution of clinical biomarkers is crucial for the early diagnosis and management of neurodegenerative diseases such as Alzheimer's disease. However, this relies on longitudinal data to capture biomarker changes over time, which is often sparse and irregular due to the high cost, labor-intensive nature, and patient burden. To address these challenges, we propose ENC-ODE, an Event-level Neurodegenerative modeling in Continuous time with neural Ordinary Differential Equations. ENC-ODE predicts future biomarker evolution by modeling clinical events through diagnosis-conditioned continuous dynamics. A target-conditioned attention mechanism weights and aggregates event-level predictions for the target time and modality without history compression. Extensive experiments on Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset demonstrate that ENC-ODE outperforms representative sequence models while offering a scalable and neuroscientifically grounded solution for clinical support. The code is available at https://github.com/JardinDelSol/enc-ode.

Early detection of dementia enables timely intervention, and reflecting cognitive impairment, spontaneous speech offers a non-invasive screening modality. Conventional approaches often focus on a single representational dimension -- such as acoustic descriptors, pause modeling, automatic speech recognition (ASR) transcripts, or multimodal fusion -- limiting integrative reasoning across heterogeneous cognitive symptoms. We propose a low-rank adaptation (LoRA)-tuned large language model (LLM) that performs structured multi-view reasoning over four complementary speech-derived signals: ASR transcripts with pause markers, discourse-level topic cues, temporal fluency statistics, and phonological sequences. These cues are encoded within a unified prompt, enabling a single LLM to learn a coherent decision function without modality-specific encoders or late-stage fusion. On ADReSSo, our best model achieves an F1-score of 90.14%, and ablation confirms the complementary contribution of each view.

Early detection of dementia through speech analysis offers a non-invasive screening alternative, but capturing both acoustic and linguistic biomarkers remains challenging. We propose a multimodal framework leveraging Whisper for dual-purpose extraction: acoustic representations from encoder outputs and transcripts via automatic speech recognition (ASR). For the acoustic pathway, temporal networks with attention pooling aggregate variable-length sequences into fixed-dimensional embeddings. For the linguistic pathway, we prompt a large language model (LLM) to extract interpretable features spanning lexical diversity, syntactic complexity, semantic coherence, and discourse patterns. A gated fusion network integrates both modalities. On ADReSS and ADReSSo, our method achieves F1-scores of 89.47% and 90.14%, demonstrating effective integration of acoustic and LLM-augmented linguistic features. Ablation shows that multimodal fusion consistently outperforms either modality alone.

Accurately predicting the spatiotemporal evolution of amyloid-$β$ and tau proteins at the individual level is critical for improving the diagnosis and treatment of Alzheimer's disease. We consider the problem of constructing patient-specific digital twins that model the propagation of these biomarkers on the cortical surface using reaction--diffusion dynamics. A major challenge is that the underlying nonlinear aggregation mechanisms are unknown and must be inferred from sparse, noisy, and heterogeneous longitudinal PET imaging data. To address this, we develop a data-driven framework that learns biomarker dynamics directly from clinical observations. The approach combines operator learning with reduced-order representations to infer governing equations of disease progression from data. Using this framework, we achieve predictive accuracies of 87% for amyloid-$β$ and 81% for tau. Building on the learned dynamics, we further formulate a PDE-constrained optimal control problem to design personalized therapeutic strategies that regulate pathological protein propagation. By integrating data-driven dynamical modeling with treatment optimization, the proposed digital twin framework provides an interpretable and predictive platform for understanding disease progression and enabling precision interventions in neurodegenerative disorders.

Longitudinal modelling of Alzheimer's disease progression is clinically useful only if it can describe not just the most likely next diagnosis, but how a patient may evolve over time and how reliable that forecast is. Most deep learning approaches reduce this problem to single-step classification, treating cognitively normal, mild cognitive impairment, and dementia as flat categories while providing limited insight into how uncertainty accumulates across future visits. We propose a probabilistic framework that combines ordinal diagnosis prediction, multi-horizon trajectory generation, and decomposed uncertainty estimation. A Temporal Fusion Transformer encoder is adapted with a CORAL ordinal output layer, asymmetric loss weighting, and converter oversampling to respect disease-stage ordering and improve sensitivity to MCI-to-dementia transitions. Conditioned on the learned patient-context representation, an autoregressive Mixture Density Network generates five-year probabilistic trajectories for diagnosis state, CDR Sum of Boxes, MMSE orientation, and hippocampal volume. On ADNI, the model outperforms linear, recurrent, and transformer baselines for next-visit diagnosis prediction, with the strongest gains on MCI-versus-dementia discrimination. Generated trajectories achieve near-nominal 90% credible interval coverage, widening uncertainty across the forecast horizon, and biomarker dynamics consistent with expected Alzheimer's disease progression. We further separate aleatoric from epistemic uncertainty using analytic mixture variance and a five-member bootstrap ensemble, which provides the strongest encoder diversity and output-level epistemic signal. Epistemic uncertainty is higher for rare progression archetypes, MCI and dementia patients, and under external evaluation on OASIS-3, where it increases alongside prediction error.

Dementia diagnosis requires integrating multi-modal clinical assessments from diverse informants and clinicians under incomplete and heterogeneous data conditions. Yet most AI-driven approaches remain Alzheimer's disease (AD)-centric, framing the problem as binary AD detection or three-stage AD progression modeling within well-curated research settings. This pathology-driven paradigm overlooks the broader, syndrome-level nature of dementia, which spans multiple stages, phenotypes, and etiologies. In this paper, we propose Dementia-Agents, a clinically aligned multi-agent framework for real-world dementia staging and phenotyping. The framework follows a three-step workflow: (1) a data agent translates structured clinical records into semantically faithful textual representations that preserve missing-data signals and routes them to domain-aligned experts; (2) five fine-tuned expert agents generate domain-level predictions; and (3) a coordinator agent performs probabilistic aggregation to produce final staging and phenotyping decisions. We develop and evaluate Dementia-Agents on a real-world clinical cohort of 1,066 patients from two cognitive neurology services. Compared with monolithic multi-modal large language models (MLLMs) and prior medical multi-agent systems, our approach achieves consistent improvements in diagnostic performance for real-world syndrome-level dementia staging and phenotyping, while preserving domain-level interpretability.

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder and a leading cause of death worldwide. Early diagnosis plays an important part especially at the Mild Cognitive Impairment stage, where timely intervention can help slow its progression before it advances to AD. Neuroimaging data, like Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) scans, can help detect brain changes early by providing structural and functional brain changes related to the disease. Yet, many multimodal models still fuse MRI and PET with static concatenation and apply identical computation to all subjects, which limits robustness to patient/site heterogeneity and can waste computation. To address these limitations, we present the first study of combining 3D convolutional feature extractors with three fusion strategies - concatenation, Gated Multimodal Unit (GMU), and gated self-attention - and a sparsely gated Mixture-of-Experts (MoE) classifier that performs input-adaptive routing, activating only the most informative experts per case. Finally, we utilize Grad-CAM to visualize disease-related regions, ensuring model interpretability. Experiments are performed across three binary classification tasks (NC vs. MCI, MCI vs. AD, and NC vs. AD). Results show that GMU achieves accuracies of 80.46 % (NC vs. MCI) and 95.47 % (NC vs. AD), while gated self-attention attains 82.08 % on MCI vs. AD. Ablations show that removing the MoE consistently degrades accuracy across all tasks. These findings underscore the value of input-adaptive, multimodal modeling for AD diagnosis by leveraging the complementary nature of MRI and PET.

The retina offers a noninvasive window into neurodegenerative disease, capturing subtle structural patterns associated with a risk of future cognitive decline. Vision-language alignment frameworks such as REVEAL have shown that pairing retinal fundus images with structured clinical risk narratives improves early prediction of Alzheimer's disease (AD). A key design choice in these approaches is the use of phenotypic grouping, where individuals with similar risk profiles are treated as multi-positive pairs during contrastive learning. However, existing methods operationalize phenotypic similarity as a discrete construct, relying on hard group assignments that impose rigid supervision and decouple group formation from representation learning. We propose a continuous formulation of phenotypic structure within contrastive learning. Rather than assigning samples to fixed clusters, we model inter-subject similarity as a differentiable weighting function derived from intra-modality embedding similarities in both retinal images and risk profiles. These weights define soft multi-positive relationships through a continuous aggregation operator, enabling graded supervision that reflects the spectrum nature of disease risk. We further introduce a soft-target contrastive objective that jointly learns cross-modal alignment and phenotypic structure in an end-to-end manner. Evaluated on UK Biobank retinal imaging data for incident AD prediction, the proposed framework consistently outperforms discrete group-based contrastive learning and standard vision-language baselines. By treating phenotypic similarity as a learnable, continuous signal rather than a fixed grouping rule, our approach provides a principled and robust foundation for population-scale neurodegenerative risk modeling from multi-modal retinal and clinical data.

Family members caring for individuals with Alzheimer's disease and related dementias (AD/ADRD) provide the foundation of long-term care worldwide. In 2023, more than 11 million U.S. family and friends contributed 18 billion hours of unpaid care, often at the cost of their own physical and mental health. These informal caregivers -- also referred as the "invisible second patients" -- experience elevated rates of mental health problems. Yet research commonly reduces their complex psychosocial experiences to a single construct of caregiver burden, obscuring which specific needs are unmet or effectively supported. At the same time, digital and AI-enabled technologies are rapidly expanding, from smartphone apps and videoconferencing to sensor platforms and AI chatbots. However, the absence of shared frameworks across medicine, psychology, and technology research limits cumulative progress. This study introduces a Caregiver Mental Health and Technology Taxonomy that systematically links AD/ADRD caregiver needs with corresponding classes of technology-based interventions. Drawing from an interdisciplinary literature review and two qualitative studies with caregivers, the taxonomy identifies mismatches between caregiver priorities and existing technological support, highlights under-served domains such as relational strain and compassion fatigue, and proposes design directions for adaptive, responsive systems. The framework offers a shared vocabulary to guide clinicians, researchers, and technology designers in developing more person-centered and clinically grounded innovation in dementia care.

Recent advances in generative machine learning models have significantly improved medical imaging, offering promising solutions for data augmentation, privacy preservation, and improved model generalization. However, synthesizing high-quality structural MRI data for Alzheimer's Disease (AD) remains challenging due to the subtle, region-specific, and progressive anatomical changes associated with neurodegeneration. In this paper, we extend the Med-DDPM conditional diffusion model -- originally designed for brain tumor synthesis -- to generate 3D structural MRIs specifically tailored to AD. We adopted Med-DDPM due to its established stability and structural fidelity compared to other generative models, which makes it particularly suitable for capturing the subtle anatomical changes characteristic of AD. Our approach conditions the diffusion process on anatomical segmentation masks derived from the ADNI dataset, incorporating key AD-relevant brain structures into the generation process. We systematically evaluate the quality and utility of the synthetic images by training segmentation models on real, synthetic, and hybrid (mixed) datasets. Experimental results demonstrate that segmentation models trained exclusively on synthetic data achieve comparable Dice scores (0.6532) to those trained on real data (0.6513), while exhibiting significantly enhanced recall. Notably, models trained on hybrid datasets (mixing real and synthetic images) outperform both real and synthetic-only baselines, achieving a Dice score of 0.7244. These findings underscore the successful use of conditional diffusion models for generating anatomically accurate, AD-specific synthetic MRIs, and highlight their potential for enhancing training data availability, improving diagnostic accuracy, and promoting research reproducibility in neuroimaging studies.

Dementia and depression are the most prevalent neuropsychiatric disorders in geriatric populations, and their overlapping symptoms pose major challenges for differential diagnosis. In this study, we investigate open-weights Large Language Models (LLMs) for predicting dementia and depression severity from speech samples collected during standardized history taking interviews with 154 German-speaking subjects. We introduce an observer-based Global Depression Scale (GDS-D) aligned with the established Global Deterioration Scale (GDS), enabling parallel global staging of affective and cognitive symptoms. We compare three LLMs (Mistral 3.1, DeepHermes, Qwen3) in two settings: (1) zero-shot prediction and (2) LLM-based feature extraction for Support Vector Regression, using human and pause-enriched transcripts. Results show that LLMs effectively predict depression severity in zero-shot settings (best MAE of 0.60), while dementia assessment benefits substantially from structured feature extraction (best MAE of 0.78), reducing errors by up to 35% over zero-shot baselines. Pause-enriched transcripts achieve competitive performance with human transcriptions, demonstrating the viability of fully automatic screening pipelines for differential neuropsychiatric assessment.

Despite increasing adoption of multimodal approaches in Alzheimer's Disease (AD) research -- aimed at integrating molecular, structural, clinical, and genetic biomarkers to enhance disease characterization -- the relationships among these modalities remain poorly understood. A systematic analysis of their dynamic interaction is essential for improving disease modeling, identifying redundant assessments, and reducing patient burden and acquisition costs. In this paper, we present a quantitative analysis of multimodal AD biomarkers by integrating tau-PET, structural MRI, cognitive scores (MMSE and CDR), and APOE4 data from 789 subjects drawn from the ADNI dataset. In our analyses, we (A) quantify cross-modal mutual information and explained variance to assess redundancy and predictive dependencies; (B) examine associations between tau topologies and structural atrophy across brain regions to select informative ROIs; (C) perform a statistical decomposition of the tau-cognition association into atrophy-related and atrophy-independent components; (D) and identify a dominant neurodegenerative trajectory that aligns with cognitive decline. This study provides a systematic characterization of cross-modal relationships, improving the interpretability and selection of biomarkers in AD. Code is publicly available at: https://github.com/antonioscardace/Multimodal-AD.

Tau positron emission tomography (PET) is widely used for the in vivo characterization of disease stage and progression in Alzheimer's disease (AD). With the adoption of multiple tau PET tracers including AV-1451, PI-2620, MK-6240 with different binding behaviors in various large-scale studies, there is a great need of effective harmonization methods to enable the cross-tracer integration of tau PET datasets. While previous methods such as CenTauR were proposed to standardize scalar tau PET measures, they are limited in accounting for the heterogeneity of tau pathology. In this work, we propose Feynman-Kac Reweighted Schrödinger Bridge Matching (FKRSBM), a surface-based framework for cross-tracer tau PET harmonization. FKRSBM learns a direct stochastic transport between tracer domains using Schrödinger Bridge matching, avoiding the Gaussian-prior routing used in diffusion-based translation. To promote biologically consistent transport, FKRSBM introduces an endpoint penalty favoring bridge pairings with matched tau-pathology status and implements it through a Feynman-Kac reweighted endpoint proposal. To preserve cortical organization, FKRSBM uses a spherical convolutional network for vertex-level harmonization on cortical surface meshes. In our experiments, we demonstrate our method by harmonizing Tau PET images acquired with the AV-1451 (n=1480) and PI-2620 (n=2458) tracers from two large-scale datasets. Compared to previous methods including ComBat, CycleGAN, Diffusion Model(DF), and unregularized Schrödinger Bridge Model(DSBM), the proposed FKRSBM method outperforms these baselines in subgroup-level alignment, tau-positivity consistency, and diagnostic classification while preserving subject-specific cortical topography of tau pathology. The code is available at: https://github.com/jianweizhang17/FKRSBM.

Alzheimer's disease (AD) progression is often described through the amyloid-tau-neurodegeneration, or AT(N), cascade. However, most longitudinal models represent this cascade either as a fixed sequence of biomarkers or as a black-box forecasting task. This makes it difficult to determine when biologically guided biomarker relationships influence future regional pathology. In this study, we introduce Bayesian Networks with Latent Time Embedding (BN-LTE), a Bayesian structural framework for stage-aware modeling of AD progression. BN-LTE estimates disease pseudotime from baseline biomarker profiles and constrains directed dependencies according to biologically plausible AT(N) ordering. Posterior spline-varying structural equations are then used to link initial multimodal measurements with future annualized regional tau-PET change. Across repeated subject-disjoint evaluations using ADNI data, BN-LTE shows strong spatial reconstruction of tau progression compared with the included forecasting baselines. Beyond spatial reconstruction, BN-LTE recovers posterior stage-varying AT(N)-constrained effects and identifies a mid-pseudotime window of amyloid sensitivity. This window is supported by model-implied g-formula contrasts, root-adjusted AIPW, mechanism-sensitive ablations, and robustness analyses across spline and prior specifications. Overall, these findings position BN-LTE as a Bayesian structural framework for forecasting tau progression while examining stage-dependent AT(N)-cascade mechanisms in observational longitudinal neuroimaging data. Our code is available at https://github.com/danleneurocom/BN-LTE.

Alzheimer's Disease (AD) is a complex neurodegenerative disorder that continues to impact millions of people worldwide. Predicting AD conversion during the prodromal stage remains critical for disease understanding and patient care. As such, survival models are widely used for AD risk prediction, yet they are typically static predictors with limited interpretability and no capacity for natural language reasoning. In this work, we propose iLENS, an interpretable large language model (LLM) guided framework based on mixture-of-experts (MoE) for survival prediction in AD conversion. Our approach uses LLM to synthesize structured neuroimaging measurements and unstructured information to guide expert routing. Our framework demonstrates competitive predictive performance and capability in patient subtyping. Furthermore, our framework provides transparent, biologically grounded rationales for its routing decisions, bridging the gap between high-performance survival analysis and interpretable clinical decision support.

This paper presents a two-stage Hybrid Classical-Quantum (HCQ) pipeline for binary Alzheimer's disease (AD) classification from 3D T1-weighted structural MRI volumes, where the classical and quantum components are designed to complement each other rather than operate independently. A supervised 3D $β$-variational autoencoder (VAE) is trained end-to-end under voxel-wise reconstruction, KL-divergence, and focal classification losses that compress each 3D MRI volume (resized from 152 x 184 x 152 to 96 x 96 x 96) into a 64-dimensional latent code. Partial Least Squares (PLS) regression selects the six components in the latent code that best separate Alzheimer's Disease (AD) from cognitively normal (CN) subjects and rescales them into rotation angles, which are encoded onto a six-qubit register using the ZZ quantum feature map to give us the respective quantum states. The input to a precomputed-kernel Support Vector Machine (SVM) is an N x N Gram matrix (N = 308), created by calculating the overlap between every pair of quantum states. The novelty of this work lies in the fact that the quantum kernel operates directly on disease-aware features that are learned end-to-end by a supervised autoencoder, rather than on pre-extracted inputs. On 308 ADNI-1 subjects, consisting of 137 AD and 171 CN subjects, the baseline achieved 67.2% accuracy and 0.759 AUC, while the stability-enhanced variant reached 72.1% accuracy and 0.799 AUC with cross-fold variance halved. 3D Grad-CAM further helped validate our model's focus on brain regions linked to Alzheimer's. The HCQ pipeline could serve as a general-purpose framework for diagnostic classification across biomedical imaging domains that present similar challenges for classical approaches.

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder that affects millions of older adults, with prevalence expected to rise significantly in the coming years. Early diagnosis, particularly during the mild cognitive impairment (MCI) stage, is critical for timely intervention. Structural Magnetic Resonance Imaging (sMRI) has emerged as a key modality for detecting AD-related brain changes, but traditional graph-based approaches often struggle with modality and inter-site heterogeneity, limiting diagnostic performance. In this paper, we propose Graph Matching Network for Alzheimer's Disease Diagnosis (GMN4AD), designed to model interactions between heterogeneous brain graphs derived from neuroimaging data. Unlike conventional methods that treat each brain graph independently, GMN4AD leverages graph matching to capture cross-graph relationships, enhancing diagnostic precision. Furthermore, we introduce a test-time domain adaptation strategy that combines contrastive learning to mitigate domain shifts during inference. Extensive experiments on three public AD datasets demonstrate that GMN4AD achieves superior performance compared to state-of-the-art methods, offering a robust and generalizable solution for AD diagnosis.

Alzheimer's disease (AD) is a fatal disorder that destroys memory and cognitive skills in the elderly population. Most treatments for AD are effective in the early stage, leading to an increasing demand for early AD diagnosis. AD diagnosis increasingly relies on multimodal data such as clinical assessments, structural Magnetic Resonance Imaging (MRI), and Positron Emission Tomography (PET) imaging. However, MRI and PET acquisition remain costly and not universally accessible, making full-modality inference impractical in real-world clinical workflows. We propose ProMUSE, a Progressive Multi-modal Uncertainty Guided Staged Evidential Network that adaptively determines when additional modalities are necessary, helping reduce the overall cost of data acquisition while maintaining accuracy. ProMUSE first performs evidential classification using low-cost clinical data and quantifies uncertainty via a Dirichlet-based subjective logic model. When uncertainty exceeds a learned threshold, ProMUSE progressively incorporates MRI or PET features, fusing modality-wise belief and uncertainty through Dempster-Shafer theory to obtain a calibrated multimodal prediction. This staged acquisition strategy enables accurate diagnosis while minimizing reliance on expensive imaging. Experiments on ADNI, AIBL, and OASIS across CN-AD, CN-MCI, and MCI-AD tasks demonstrate that ProMUSE achieves competitive or superior accuracy compared to full-modality baselines while reducing MRI/PET usage by 50-90%, yielding substantial cost savings. These results highlight ProMUSE as a practical, uncertainty-aware, and resource-efficient solution for real-world AD screening.

Voice-based screening offers a scalable and non-invasive way to assess neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), but their staging remains challenging due to the difficulty of integrating heterogeneous data. This paper presents NeurMLLM, an efficient multimodal generative framework for neurodegenerative disease staging. NeurMLLM first encodes the spectrograms and Mel-frequency cepstral coefficients of audio data with vision transformers and projects their representations into the embedding space of a large language model (LLM), where they are concatenated with transcript and demographic instruction tokens as a single unified sequence. The LLM is then instruction-tuned via Low-Rank Adaptation using task prompts to autoregressively predict a constrained label token, enabling a generative classification. By evaluating on the Bridge2AI-Voice dataset for fine-grained staging of AD and PD, we observe that NeurMLLM achieves strong performance, consistently outperforming classical machine learning methods and existing LLM-based approaches. The results show the high potential of multimodal LLMs in neurodegenerative disease staging, improving staging accuracy and supporting accessible deployment.

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.

Early detection of neurodegeneration remains a critical clinical challenge. This study investigates whether sleep EEG signal criticality, quantified via Multifractal Detrended Fluctuation Analysis (MFDFA), serves as a non-invasive biomarker for future cognitive decline. We analyzed longitudinal data from the National Sleep Research Resource (NSRR) Study of Osteoporotic Fractures (SOF) cohort, comparing baseline sleep EEG dynamics between women who remained cognitively normal and those who later progressed to dementia-related impairment ($3MS < 78$).Our results reveal significant group-level differences in Hurst exponent $H(q)$ distributions, particularly during non-REM stages N2 and N3. Cognitively healthy individuals exhibited signal dynamics significantly closer to an optimally critical state across all electrode locations ($p \leqslant 0.001$), supporting the Brain Criticality Hypothesis. Supervised UMAP projections confirmed clear spatial separation between groups throughout the overnight sleep architecture.The dementia group demonstrated a shift in DFA exponents toward $1.0$, suggesting that a reconfiguration of scale-free neural dynamics during sleep precedes clinical symptoms. These findings highlight the potential for MFDFA-derived measures to be integrated into automated, sleep-based screening tools, enabling earlier preventative interventions during the prodromal window of dementia.

Supervised fine-tuning with synthetic rationale data is widely assumed to improve language model performance on clinical prediction tasks by teaching models not just what to predict but why. We test this assumption on five-year Alzheimer's disease and related dementias (ADRD) prediction from longitudinal health histories. Across a large-scale controlled experiment of 504 configurations, we find that rationale-based SFT consistently and substantially hurts prediction performance relative to label-only fine-tuning. The degradation persists across model families and data scales, and is not resolved by using a reasoning-oriented base model. Crucially, the failure is not explained by poor rationale quality: human expert annotation confirms that the generated rationales are medically accurate and faithfully grounded in patient-specific evidence, and few-shot experiments show that the same rationales improve performance when used as inference-time demonstrations rather than training targets. We identify the root cause as a structural conflict between narrative plausibility and discriminative optimization. We hope our work paves the path toward a more precise understanding of when and how rationale-based supervision helps and when it does not, guiding the responsible development of language models for high-stakes clinical prediction.

Alzheimer's disease (AD) progression is highly heterogeneous and is typically observed through sparse and irregular longitudinal data, posing challenges for prediction and personalised monitoring. Existing machine learning approaches have improved AD prediction using multimodal data, yet often focus on static classification or cohort-level risk estimation, providing limited support for subject-specific modelling and uncertainty-aware reasoning. To address these limitations, we present a personalised digital twin framework for AD prediction and scenario-based analysis using multimodal longitudinal data. The proposed approach integrates complementary modelling strategies to capture clinical transitions and temporal dependencies across visits. Using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitive assessments, clinical variables, and MRI-derived phenotypes, the framework predicts cognitive status and diagnostic categories while quantifying predictive uncertainty and enabling patient-specific what-if trajectory analysis. Evaluation on leak-free subject-level splits demonstrates strong performance in score forecasting and diagnosis classification. In this sparse and irregular ADNI setting, transition-based modelling of adjacent visits achieved higher predictive accuracy than the sequence-based branch, suggesting that local transition modelling may be more data-efficient. While sequence models remain valuable for uncertainty-aware trajectory forecasting, local transition modelling offers a more data-efficient and robust predictive strategy. These findings highlight the importance of aligning temporal modelling strategies with clinical data structure and suggest that transition-based digital twin formulations may provide a practical and interpretable approach for personalised disease forecasting in neurodegenerative disorders.

Alzheimer's disease is a progressive neurodegenerative disorder, and its progression varies substantially across patients. Existing work aims to forecast patients' future cognitive state, with minimal focus on reconstructing the state from past visits. Furthermore, in current research, quantifying predictive uncertainty remains underexplored and relies on costly modalities such as MRI, PET, and CSF, limiting their deployment in resource-limited settings. In this research, our primary objectives are: First, bidirectional prediction of cognitive scores from irregular visits to present the complete disease trajectory. Second, to enable interpolation and extrapolation capabilities to assist clinicians in informed prognostic decision making, and third, to provide a well-calibrated uncertainty estimate for all predictions, and finally, to achieve the objectives using the modalities available during routine visits. We propose a unified framework, GNOVA: A GRU-Neural ODE Variational Autoencoder. The architecture combines a Gated Recurrent Unit encoder and a Neural ODE decoder within a variational autoencoder framework. In our work, we forecast the CDR-SB and MMSE Scores. The GRU encoder allows for any number of inputs at any time point. The Neural-ODE decoder performs continuous estimation, allowing interpolation and extrapolation at any desired time point. The Variational autoencoder allows for uncertainty estimation in predictions. We worked with 1,727 patients from the ADNI dataset over 10 years; the model achieved mean absolute errors of 1.35 and 2.28 for CDR-SB and MMSE scores, respectively, without requiring any neuroimaging or biomarker data. Feature-ablation studies revealed that age, BMI, and APOE4 status were strong predictors. The proposed framework enables the reconstruction of incomplete patient histories and the anticipation of future cognitive states.

Neurodegenerative disorders such as Alzheimer's disease exhibit highly organized patterns of regional brain vulnerability, yet the biological mechanisms underlying this spatial selectivity remain incompletely understood. Existing imaging-transcriptomic studies have largely relied on correlation-based analyses between gene expression and neuroimaging phenotypes, limiting their ability to model how molecular organization gives rise to neurodegeneration. Here, we introduce a cross-scale spatially-aware generative framework for modeling transcriptomic programs underlying cortical neurodegeneration. Regional transcriptomic profiles were derived from the Allen Human Brain Atlas using 910 landmark genes across 68 cortical regions. Neurodegenerative vulnerability maps were constructed from ADNI FreeSurfer cortical thickness measurements by computing regional cortical thinning differences between cognitively normal controls (NC = 926) and Alzheimer's disease subjects (AD = 426). A variational generative architecture was used to learn latent biological programs linking regional gene-expression organization to cortical degeneration while incorporating graph-based spatial smoothness regularization to preserve cortical organization. The proposed framework achieved strong prediction of regional neurodegenerative vulnerability, yielding an explained variance of 0.8604 and a significant spatial correlation between predicted and observed cortical degeneration profiles (r = 0.9439, p < 0.001). The learned latent representations revealed structured transcriptomic organization associated with distributed disease susceptibility. These findings demonstrate that biologically constrained generative modeling can bridge microscale molecular organization with macroscale neurodegeneration, providing a foundation for spatially-aware generative neurobiology and computational neuroscience.