Alzheimer's Disease

The corpus callosum (CC) is a major white-matter structure and a well-established marker of brain aging, but most studies quantify it using scalar summaries that discard its boundary geometry. We present a Riemannian shape-space framework for analyzing age-related morphological change in the midsagittal CC, applied to the OASIS-1 cohort. Each contour is represented by $128$ landmarks and embedded into Kendall shape space, where translation, rotation, and scale are removed. We derive a multivariate geodesic regression with exact Riemannian gradients and use the fitted age-velocity field to localize age-related deformation to five anatomical sub-regions. In the cognitively normal cohort ($n = 252$), geodesic regression outperforms the Euclidean linear benchmark ($R^2 = 0.1355$ vs.\ $0.1216$). Regional energy is posterior-dominant: the Splenium carries $41.4\%$ and the Isthmus $23.8\%$ of total age-related shape change, together accounting for $\sim 65\%$ despite comprising only $\sim 35\%$ of landmarks. Signed projections confirm the ordering (Splenium $r = 0.570$; Isthmus $r = 0.473$). In contrast, age explains less than $0.5\%$ of shape variance in Alzheimer's disease ($n = 88$), indicating that the disease disrupts the healthy aging trajectory. A tangent-space classifier achieves an age-group AUC of $0.791$ from the 2D contour alone, exceeding a recent volumetric benchmark ($0.67$).

Dementia affects an estimated 57 million people worldwide, and for most families the hardest part of care is not memory loss but the behavioral and psychological symptoms of dementia (BPSD): agitation, wandering, resistance to care, sundowning. Understanding these symptoms requires more than recognizing the behavior itself; it also requires knowing what happened beforehand. The same behavior may call for a different response depending on its trigger. Video-language models (VLMs) could potentially support caregivers, yet no existing benchmark evaluates this capability. To fill this gap, we present DementiaCare-Bench: 56 professionally produced caregiver training videos segmented into 94 clips across nine BPSD categories, with 2023 questions generated by a multi-agent pipeline that grounds every clinical claim in a verbatim transcript span. Each question is then probed under four visual conditions and labelled by the least it requires, so its visual demand is measured rather than assumed. Measurement contradicts intent: we wrote 77.7% of the questions to require ordered frames, and 34.8% do. Across 12 current VLMs the pattern is uniform. The best reach 85% overall, but that average is carried by questions a language model can answer from clinical knowledge alone; accuracy falls by 17 points on average on questions that require the ordered clip, and a leading open model scores at chance on judging whether a caregiver's response was appropriate. A lightweight LoRA fine-tune, DemCare-VLM, moves video dependence from -3.3 to +4.5 points, so what the benchmark exposes can be repaired and not only measured.

Brain age estimation has become a popular research proxy for assessing brain health and disease, yet longitudinal trajectories of brain ageing are still poorly defined, and clinical use is limited. Building on existing Siamese longitudinal frameworks, we develop Brain-Predicted Age Acceleration (Brain-PACE) to directly estimate the pace of structural brain ageing from paired T1-weighted MRI. Brain-PACE identified accelerated ageing in $42.6$% of participants with mild cognitive impairment. Faster Brain-PACE was associated with greater functional and cognitive impairment (FAQ; $r=0.35$, ADAS13; $r=0.30$, CDR-SB; $r=0.32$) and greater regional tau burden in the posterior cingulate ($r=0.59$), precuneus ($r=0.47$), and entorhinal cortex ($r=0.37$). These associations were stronger than those observed when pace was calculated indirectly from repeated cross-sectional brain age estimates, suggesting that direct longitudinal modelling captures complementary information relevant to ongoing pathological change. Methodologically, Brain-PACE extends the LILAC framework by combining spatial attention with soft label distribution learning and a Cram'er distance objective, improving probabilistic performance and reducing prediction bias while providing measures of predictive uncertainty. Together, these findings support Brain-PACE as a complementary longitudinal imaging phenotype with sensitivity to relevant clinical and biological changes in early neurodegeneration.

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.

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.

As populations age, cognitive decline from mild cognitive impairment (MCI) to dementia is a defining health challenge of the coming decades, yet routine assessment often misses its earliest signs. This article critically synthesizes recent technological advances for detecting and managing cognitive impairment in older adults, spanning neurophysiological signals (chiefly electroencephalography, EEG), structural and molecular neuroimaging (MRI and amyloid/tau PET), blood-based biomarkers, and digital markers, integrated through artificial intelligence (AI), machine learning (ML), and deep learning (DL). Beyond summarizing, it contributes a cross-disciplinary taxonomy, a methodological-rigor lens foregrounding subject- and site-independent validation, an integrative early-detection framework linking tiered screening to intervention, and comparison tables of detection methods, interventions, and risk and protective factors. EEG markers (alpha/theta changes, P300 latency) and deep models (CNNs, LSTM/BiLSTM, transformers, self-supervised EEG foundation models) report strong accuracy, yet many rest on small, single-site datasets unlikely to survive rigorous external validation. Elsewhere, gains are tangible: plasma p-tau217 has reached clinical utility, with the first blood test cleared to aid Alzheimer's diagnosis in 2025; anti-amyloid therapies (lecanemab, donanemab) are approved despite modest, contested benefits; and multidomain lifestyle prevention has matured. Wearable, remote, speech, and virtual-reality tools enable continuous, ecologically valid monitoring, and multimodal fusion improves sensitivity and specificity. Barriers remain: standardization, explainability, data privacy, and equitable, externally validated deployment. The field's near-term promise lies in trustworthy, multimodal, longitudinally validated systems linking early detection to actionable, personalized care.

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.

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.

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 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.

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.

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.

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.

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.

Early and accurate detection of Alzheimer's disease (AD) is important for timely intervention and disease management. Generalized Eigenvalue Proximal Support Vector Machine (GEPSVM) and its Universum-based variants have shown promising results for AD classification. However, existing methods treat Universum samples as independent points and do not consider the geometric relationships among them. This paper proposes two graph-guided Universum learning models, namely UG-GEPSVM and IUG-GEPSVM, for AD versus cognitively normal (CN) classification using structural MRI data. In the proposed framework, mild cognitive impairment (MCI) subjects are used as Universum data to provide intermediate information between AD and CN classes. A graph is constructed over the Universum samples using Gaussian similarity, Minimum Spanning Tree connectivity, and multi-hop propagation. From this graph, a Laplacian matrix is derived that captures the geometric structure of the MCI samples. This Laplacian-based regularization is incorporated into the learning process in place of the conventional independent Universum penalty term. UG-GEPSVM integrates this regularization into the generalized eigenvalue formulation, while IUG-GEPSVM extends the numerically stable improved GEPSVM framework using a standard eigenvalue formulation. Experiments on ADNI MRI dataset variants using ICA- and PCA-based features at five different noise levels show that both proposed models consistently outperform existing GEPSVM and Universum-based methods. UG-GEPSVM achieves the highest average AUC of 88.07% and maintains stable performance under increasing noise levels. Statistical tests further confirm the significance of the observed improvements.

Understanding how structural connections are associated with tau propagation in Alzheimer's disease (AD) remains a central open question, yet existing computational models either rely heavily on biophysical assumptions or lack neurobiologically interpretable pathway maps. We present SC-TauPath, a structural connectivity (SC) attribution framework that maps tau propagation pathways from in vivo neuroimaging data. SC-TauPath combines a Network Diffusion Model (NDM)-augmented multilayer perceptron with gradient $\times$ input attribution to score each SC edge's contribution to tau prediction, then translates these attribution scores into multi-scale pathway maps (backbone edges, high-traffic routes, and hub ROIs), which validates established Braak staging anatomy. Applied to 234 ADNI participants with paired DTI SC and 18F-Flortaucipir PET, SC-TauPath achieves strong cross-validated tau prediction and yields attribution-based pathway maps consistent with established Braak staging anatomy, demonstrating that SC encode spatially specific information about regional tau distribution in AD.

Predicting whether an individual with Alzheimer's disease will experience mild or severe disease progression is essential for personalized treatment. Typically, practitioners seek to predict the distribution of a discrete disease score, conditional on an individual's current MRI volume and their historical disease trajectory. Classical statistical regression models and single-task neural networks are not well-suited for this purpose because fitting separate models is infeasible (since each individual typically has few observations), while ignoring individual-level correlation leads to poor generalization. Meta-learning, in contrast, provides a natural avenue to dynamically predict distributions without retraining and model nonlinear relationships between the outcome and covariates. Motivated by this, we propose a Bayesian meta-learner that is trained on multiple individuals but tailors the predictive disease score distribution to each individual's historical data. Our model predicts on unseen individuals without retraining, scales linearly with the number of historical observations, and is guaranteed to be less overconfident when predicting long-term disease scores compared to its deterministic counterpart. On real-world data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, our model achieves performance competitive with both single-task models and deterministic meta-learners, while substantially improving performance when predicting long-term disease progression.

Mild cognitive impairment (MCI) and subjective cognitive decline (SCD) are closely associated with the early Alzheimer's disease continuum, where accurate and explainable diagnosis is important for early risk assessment and intervention. Existing connectome-based deep learning models can improve classification performance but often provide limited insight into disease-related functional and structural connectivity changes. This paper proposes an atlas-knowledge-guided Generative Counterfactual Attention-guided Network (GCAN) for explainable cognitive decline diagnosis using multimodal brain connectomes. GCAN formulates diagnosis as a source-to-target counterfactual generation problem, where target-label connectomes are generated from source-label inputs and their differences are used to construct counterfactual attention maps. To preserve connectome topology, an Atlas-aware Bidirectional Transformer (AABT) performs network-level token encoding and decoding under brain-atlas constraints. The framework is further extended from functional connectivity (FC) to joint functional and structural connectivity (SC) modeling, enabling counterfactual analysis of complementary functional reorganization and structural topology changes. Experiments on hospital-collected and ADNI datasets show that GCAN achieves competitive performance across HC vs. SCD, HC vs. MCI, and SCD vs. MCI classification tasks. Visualization, circular connectome analysis, CAM-based comparison, ablation studies, and confidence interval analysis further support the interpretability and reliability of the proposed framework. Modality-specific FC and SC pre-trained classifiers are used to provide target-state priors for counterfactual generation while being separated from the downstream diagnostic classifier to prevent data leakage.

Financial exploitation is a growing concern for people with Alzheimer's disease, especially during periods of reduced cognitive stability. Conventional fraud detection systems usually rely on financial behavior alone and ignore clinically relevant factors that may alter vulnerability. This paper proposes a medication-aware framework that synchronizes medication adherence with transaction-level monitoring to improve detection of cognitively risky financial events. A hybrid simulation dataset was constructed for 180 patients across 45 days, producing 8,100 medication records and 30,855 transactions. The framework evaluates amount anomaly, vendor novelty, transaction frequency, time deviation, and medication adherence through financial-only, additive medication-aware, and interaction-aware logistic models. Results show that the financial-only baseline obtained the highest global F1-score of 0.5000, but the interaction-aware model improved recall during medication-induced vulnerability windows from 0.7442 to 0.9070 and achieved the highest average precision for ranked high-risk cases. The findings suggest that medication adherence is most useful as a contextual modifier of financial risk rather than as an isolated predictor.

Learning from 3D meshes is challenging because the data reside on non-Euclidean surfaces embedded in 3D space. This is particularly evident in domains such as brain cortical surface analysis, where existing models typically rely on ROI-agnostic, face-based, or fixed-size patches. Such patches can duplicate boundary vertices, conflate anatomically distinct regions, or incorporate non-cortical vertices such as those of the medial wall. We develop variable-size supervertex (vSV) partitioning, which groups cortical surface vertices into vSV patches similar to superpixels in images. Building on these vSVs, we design Variable-size SuperVertex Vision Transformer (vSV-ViT), a Vision Transformer that processes vSVs through padding, mask-aware patch embedding, and vertex position embedding. We demonstrate the benefits of the proposed framework through a quantitative analysis of vertex assignment in surface partitioning and downstream tasks using Alzheimer's disease brain image datasets. For downstream tasks, we use meshes of cortical thickness and cortical curvature as input to various encoder models and evaluate classification performance. The superior predictive accuracy of vSV-ViT over recent surface-based models supports its effectiveness for cortical surface learning, with AD-related and sex prediction serving as downstream validation. Extending the framework to other cortical surface applications and broader 3D mesh domains remains future work. Code is available at https://github.com/labhai/vSV-ViT.

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.

Structural MRI-to-amyloid PET synthesis has been proposed as a non-invasive alternative for amyloid assessment in Alzheimer's disease (AD). However, reported performance of identical models varies widely across studies, and increasingly complex architectures have not led to consistent gains. This inconsistency is thought to be caused by a fundamental biological ambiguity: MRI captures neurodegeneration, while PET measures amyloid pathology - two processes that are often temporally decoupled in AD. As a result, similar MRI patterns may correspond to different amyloid states, creating ambiguous one-to-many mappings. MRI-to-amyloid PET synthesis may therefore be intrinsically ill-posed; however, this idea has yet to be tested scientifically. The aim of this work is to test this hypothesis through two controlled experiments. We first control the training distribution by stratifying paired MRI-PET data by amyloid and neurodegeneration status. Using two standard synthesis models under a controlled design, we show that biologically unambiguous mappings are learnable in isolation, but performance collapses when data ambiguity is introduced. This demonstrates that ambiguity in the data distribution, rather than architectural capacity, constrains performance. Second, we show that introducing orthogonal biological information in the form of plasma biomarkers resolves this ambiguity. When multimodal inputs are incorporated, performance improves and stability is restored. Together, these findings suggest that limited and inconsistent performance in MRI-to-amyloid PET synthesis is explained by intrinsic biological ambiguity, and that stable, meaningful progress requires multimodal integration rather than architectural complexity.

Individuals with Alzheimer's disease (AD) and Alzheimer's disease-related dementia (ADRD) experience memory and thinking changes that impact their ability to use digital daily management tools. For example, adding an event to a digital calendar requires multiple steps that may act as barriers to independent use for individuals with AD/ADRD. This paper presents AI-Care, a conversational agentic artificial intelligence (AI) layer built on top of a remote caregiving platform co-designed with people with AD/ADRD. AI-Care is designed to reduce the cognitive load on individuals with AD/ADRD when managing everyday tasks such as setting calendar reminders and organizing to-do lists through natural-language interaction with a voice-first chatbot. The system uses a LangGraph-based stateful orchestration approach in which each request passes through sanitization, intent classification, context loading, safety checks, deterministic slot collection, tool execution, and response composition. Safety-critical responses, particularly around medications and allergies, are grounded in caregiver-verified records rather than free-form model generation. The system does not make autonomous medical or treatment decisions. Incomplete or ambiguous requests are handled through controlled multi-turn clarification rather than silent failure or guessing. The system supports both typed and spoken input, with voice output through ElevenLabs text-to-speech. Longer responses are chunked before synthesis to avoid rushed playback. A preliminary pilot with four individuals with mild-to-moderate AD/ADRD showed that users found the system trustworthy, competent, and likable, and were able to complete the evaluated coordination tasks through conversation. We describe the design goals, system architecture, safety controls, and findings from this formative evaluation.

Medium-horizon Alzheimer's disease progression prediction is difficult because future clinical scores can remain tied to baseline severity, while biomarker histories are irregular and incompletely observed. We develop an anchor-based analysis of 24-month Clinical Dementia Rating Sum of Boxes (CDR-SB) change using harmonized Alzheimer's Disease Neuroimaging Initiative (ADNI) tables. Each labeled sample is anchored at a mild cognitive impairment visit, uses only clinical and biomarker history observed at or before that anchor, and defines the response as CDR-SB at the future visit closest to 24 months within an 18--30 month window minus anchor CDR-SB. The analytic cohort contains 2,600 labeled anchors from 858 participants and 7,276 longitudinal rows. We propose a residual gap-aware transformer that combines a mixed-effects statistical reference with transformer-based residual learning from pre-anchor clinical and biomarker histories. The model uses participant-level random intercepts in the mixed-effects reference, observation-level triplet tokenization for irregular histories, and a learned nonnegative time-gap penalty inside self-attention. We compare the proposed model with a Bayesian-information-criterion-selected linear mixed-effects baseline, GRU-D, and STraTS under repeated participant-level train--test splits. Across five participant-level random seeds, the proposed model achieves the best mean test performance across all reported metrics, reducing MSE by 13.1% and increasing prediction--observation correlation by 26.4% relative to the mixed-effects baseline. It also improves over both GRU-D and STraTS in mean error and correlation. These results show that statistical anchoring and gap-aware residual learning provide a useful structure for medium-horizon Alzheimer's disease progression prediction.

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.

The systemic, metabolic, lifestyle factors have established associations with Alzheimer's Disease (AD) through epidemiologic and AD-specific biomarker studies. Whether colored fundus photography (CFP) contains retinal structural signatures corresponding to these AD-related risk domains remains unclear. To determine whether deep learning (DL) models can predict 12 AD-related risk factors from CFP and to characterize the retinal structures underlying these predictions, thereby assessing whether CFP reflects pathways to AD vulnerability. Using 62,876 CFPs from 44,501 unique participants from the UK Biobank, DL models were trained to predict 12 factors linked to AD incidence: 6 categorical (sex, smoking, sleeplessness, economic status, alcohol use, depression) and 6 continuous (age, age at completing education, BMI, systolic, diastolic blood pressure, HbA1c). Model performance, model saliency, and saliency-derived scores (CAM-Score) were evaluated and compared to retinal morphometry. The scores were also compared between incident-AD cases (average 8.55 years before onset) and matched controls. Performance of DL ranged from AUROC= 0.5654-0.9480 for categorical and R2=-0.0291-0.7620 for continuous factors, outperforming most of the morphometry-machine learning models. Saliency-based score consistently highlighted biologically meaningful regions, particularly the optic nerve head and retinal vasculature. It also aligned with present morphometric variations. Several saliency-based scores differed significantly between incident AD and matched controls, suggesting potential overlap between retinal correlates of risk factors and preclinical AD-associated changes. CFP encodes retinal signatures linked to AD risk factors. Although not diagnostic, DL-derived retinal representations may uncover biologically meaningful risk-related structural changes mirroring the potential AD vulnerability.

Individualized Alzheimer's disease (AD) progression prediction requires models that use irregular visits, account for censoring, avoid diagnostic leakage, and provide calibrated horizon risks. We propose PROgression-aware MultI-horizon Survival Estimation for Alzheimer's Disease (PROMISE-AD), a leakage-safe survival framework for predicting conversion from cognitively normal (CN) to mild cognitive impairment (MCI) and from MCI to AD dementia using ADNI/TADPOLE tabular histories. PROMISE-AD converts pre-index visits into tokens with standardized measurements, missingness masks, longitudinal changes, time-normalized slopes, visit timing, and non-diagnostic categorical attributes. A temporal Transformer fuses global, attention-pooled, and latest-visit representations to estimate a progression score and latent discrete-time mixture hazards. Training combines survival likelihood, horizon-specific focal risk loss, progression ranking, hazard smoothness, and mixture-balance regularization, followed by validation-set isotonic calibration for 1-, 2-, 3-, and 5-year risks. In held-out testing across three seeds, PROMISE-AD achieved an integrated Brier score (IBS) of 0.085 $\pm$ 0.012, C-index of 0.808 $\pm$ 0.015, and mean time-dependent AUC of 0.840 $\pm$ 0.081 for CN-to-MCI conversion, yielding the lowest IBS among compared methods. For MCI-to-AD conversion, PROMISE-AD achieved the highest C-index (0.894 $\pm$ 0.018) and near-ceiling 5-year discrimination (AUROC 0.997 $\pm$ 0.003; AUPRC 0.999 $\pm$ 0.001), although some baselines had lower IBS. Ablations and interpretability supported longitudinal change features, fused temporal representations, mixture hazards, cognitive and functional measures, APOE4 status, and recent conversion-proximal visits. These findings suggest that progression-aware survival modeling can provide interpretable multi-horizon AD conversion risk estimates.