Cleaner Speech, Weaker Generalization: Revisiting Pitt-Derived Benchmarks for Alzheimer's Disease Detection

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.

GraM-Diff: A Unified Graph-Mamba Diffusion Framework for EEG-Based Alzheimer's Disease Data Generation and Diagnosis

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.

Leveraging a Foundation Model for the EEG-Based Diagnosis of Alzheimer's Disease

Biological heterogeneity in Alzheimer's Disease (AD) poses a critical diagnostic challenge, particularly for traditional linear methods that fail to capture non-linear neural dynamics. To address this, we propose a diagnostic framework utilizing the Large Brain Model (LaBraM), pretrained on over 2,500 hours of EEG data. By integrating these high-dimensional latent embeddings with a non-linear Random Forest classifier, our approach effectively isolates robust disease markers. Under a rigorous subject-independent 5-fold cross-validation protocol, the method achieves an ROC-AUC of 89.36% +/- 3.49%, PR AUC of 81.45% +/- 4.43%, and Balanced Accuracy of 82.44% +/- 4.34% in distinguishing dementia patients from healthy controls. Notably, this performance uses only 8-second EEG segments, surpassing traditional spectral baselines, including band-power and parameterized oscillatory features (FOOOF). Post-hoc occlusion analysis confirms the model captures clinically validated biomarkers, specifically occipital-frontal Alpha and Theta rhythm degradation. Additional neurophysiological alignment analysis demonstrated that higher LaBraM-predicted dementia probability significantly correlated with worse cognitive performance, greater clinical severity, increased theta and alpha relative power, and higher aperiodic exponent. These findings demonstrate that deep latent representations extract clinically relevant signatures from noisy signals, enabling precise, rapid, and data-efficient diagnosis.

PANDA - Prototype-Anchored Alignment for Partially Unpaired Multimodal Learning, with Applications to Alzheimers MRI and TCGA Pathology

Multimodal medical prediction often faces incomplete pairing: auxiliary modalities with complementary signal are available for only a subset of subjects (or none) and cannot be assumed at deployment. We introduce PANDA (Prototype Anchored Data Alignment), a two-stage framework that transfers auxiliary information to a primary-modality model without auxiliary inputs at inference. Stage 1 learns a shared embedding from the paired subset and estimates class prototypes from auxiliary modalities; Stage 2 trains the primary encoder on all subjects using cross-entropy plus alignment to the frozen prototypes. Because supervision is defined at the class-prototype level, PANDA accommodates arbitrary pairing rates, including zero subject overlap. We evaluate PANDA on two applications. On a 1,021-subject multi-scanner ADNI cohort, we perform AD/CN classification with three auxiliary modalities at distinct pairing rates: tabular scores (44.8%), FDG-PET (18.7%), and external handwriting kinematics (0% overlap). Relative to the same-backbone MRI-only baseline, PANDA attains AUC 0.868 +-0.020 (+7.9pp) and reduces 1.5T CN false positives by 24.3pp; on a fully trainable Conv5-FC3 backbone it reaches AUC 0.893 (best overall). A pairing-rate ablation shows that the joint anchor remains within seed noise from 75% to 5% pairing. On TCGA-Lung survival prediction from whole-slide images with RNA-seq as auxiliary data, PANDA improves over WSI-only on 2-year OS (AUC +3.5pp) and Cox PH (C-index +9.0pts) and outperforms full-fusion training, which underperforms WSI-only, while requiring no RNA at inference; wide confidence intervals on this smaller cohort keep the gains below conventional significance. Overall, PANDA provides a deployment-oriented mechanism for leveraging incomplete auxiliary modalities to improve primary-modality prediction.

MSR-IVA: Masked Structural Residual Independent Vector Analysis for State-Aware Fusion of Structural MRI and Dynamic Functional Network Connectivity

Multimodal fusion of structural MRI (sMRI) and dynamic functional network connectivity (dFNC) can reveal how brain structure relates to changing functional states. When the same structural latent representation is coupled with multiple states, applying independent vector analysis (IVA) separately to each state can produce unrelated structural decompositions, while forcing identical decompositions may suppress state-specific relationships. In addition, not every subject expresses every dynamic state. We propose masked structural residual IVA (MSR-IVA), a state-aware framework that combines a shared structural representation with state-specific residual adaptations and masks for incomplete state expression. On an Alzheimer's Disease Neuroimaging Initiative cohort, MSR-IVA improved matched source coupling by 6.5% and reduced unmatched dependence by 15.7% relative to the independent pairwise IVA baseline. Among subjects expressing both states, mean absolute cross-state structural source correlation was 0.9177 for MSR-IVA versus 0.2978 for no sharing, demonstrating controlled structural sharing that preserves source correspondence while allowing state-specific adaptation.

Spending Scarce Confirmatory PET Measurements: Target-Aligned Validation in A4/LEARN

Anti-amyloid therapies and blood-based biomarkers are changing Alzheimer disease workups into a two-stage measurement workflow: screen broadly with cheaper information, then spend scarce confirmatory amyloid measurements where they support the decision that will be reported. Amyloid positron-emission tomography (PET) remains one such protocol measurement for amyloid burden, but PET slots, trial budgets, and payer-facing evidence packages are finite. This paper asks a deliberately operational question: when is simple transparent PET validation enough, and when is a fitted residual-uncertainty score worth the added complexity? For a weighted protocol target, the first-order value of validating subject i is the product of target influence and residual protocol uncertainty. Generic uncertainty sampling uses only the second factor and can spend PET measurements on subjects that are hard to predict but weak for the scientific, clinical, or commercial claim. We apply this rule to the A4/LEARN PET archive, treating observed PET as a design laboratory for scarce-confirmation studies. For the primary APOE4 carrier versus non-carrier contrast in Centiloid 24-or-higher PET positivity, simple APOE4-balanced validation recovers nearly all of the target-specific gain: at PET budget 200, the confidence-interval width ratio relative to random validation is 0.923 for APOE4 balancing and 0.914 for target-specific scoring, while generic uncertainty sampling is 0.980. Other targets behave differently: target-specific scoring gives larger gains for an age-slope analysis and for cutoff-indexed PET positivity. The practical message is simple: spend scarce protocol measurements according to the claim being validated, not only according to prediction uncertainty.

Modality Contribution Score - A Per-Patient Framework for Quantifying the Relative Diagnostic Contribution of Structural MRI and Amyloid PET in Alzheimer's Disease

Multimodal neuroimaging combining structural MRI and positron emission tomography (PET) captures complementary structure-function relationships across the Alzheimer's disease (AD) continuum, yet existing artificial intelligence systems produce a single diagnostic label without quantifying which imaging modality drove that decision for a specific patient. We introduce the Modality Contribution Network (MCNet) and the Modality Contribution Score (MCS), the first per-patient attribution framework quantifying the shift in modality dominance from structural atrophy to amyloid and metabolic dysfunction across the cognitively normal to MCI to AD continuum. MCS is normalised to unity per subject via modality ablation (MCS_MRI_i + MCS_PET_i = 1.0 for every subject i), providing an interpretable, clinically actionable score that fluid biomarkers cannot supply. Applied to 327 ADNI-3 participants balanced across cognitively normal, mild cognitive impairment, and AD groups, MCNet achieved competitive three-class staging performance (AUC=0.881). The MCS revealed a statistically significant monotonic gradient (Kruskal-Wallis p<0.0001), with increasing PET dominance from cognitively normal (MCS_PET 0.412+/-0.229) through MCI (0.489+/-0.289) to AD (0.671+/-0.426), validated against amyloid SUVR (r=0.172, p=0.006) and FDG metabolic biomarkers (r=-0.287, p=0.0005) from separate imaging pipelines. External replication in 1,073 independent OASIS-3 subjects confirmed cross-cohort generalisability (H=166.99, p<0.0001, eta^2=0.156). A mechanistic comparison with SHAP demonstrated that ablation-based MCS captures clinically meaningful modality dependence that deviation-based methods cannot. These findings position MCNet as a foundation for personalised imaging decisions, clinical trial stratification, and trustworthy AI in dementia care.

Longitudinal Bayesian Learning of Continuous Disease Position across the Alzheimer's Disease Continuum

Alzheimer's disease (AD) progresses as a continuous biological process, whereas most existing neuroimaging-based artificial intelligence methods remain limited to discrete diagnosis or clinical score prediction from cross-sectional imaging. In this work, we propose Disease Continuum Positioning (DCP), a longitudinal Bayesian Learning framework that continuously estimates disease severity from longitudinal diffusion tensor imaging (DTI). Specifically, DCP models disease severity as a low-dimensional probabilistic latent variable by jointly integrating longitudinal observations with weak clinical supervision, from which the proposed Disease Continuum Score (DCS) is derived to quantify an individual's position along the Alzheimer's disease continuum together with its associated uncertainty. Extensive experiments on the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort demonstrate that DCP consistently outperforms representative disease progression methods. More importantly, comprehensive validation analyses show that DCS accurately characterizes disease severity, exhibits strong clinical relevance, preserves longitudinal disease evolution, and predicts future disease conversion. These results suggest that DCS provides a quantitative imaging-derived representation for continuous assessment of Alzheimer's disease progression beyond conventional diagnostic labels and clinical scores.

Delta2Gamma: Band-Wise Adaptive Contrastive Learning of EEG for Alzheimer's Disease Detection

Low-cost, scalable screening for dementia remains an open problem. Imaging-based diagnosis is costly and hard to deploy widely. Electroencephalography (EEG) is portable and inexpensive, but its recordings are noisy, vary widely across subjects, and carry few clinical labels. We tackle this with Delta2Gamma, a self-supervised framework that learns EEG representations from unlabeled data by contrasting augmented views of each signal. Rather than treat EEG as a single stream, Delta2Gamma decomposes every recording into the five canonical neural rhythms (delta, theta, alpha, beta, gamma). Each band gets its own encoder and projection head. Each also gets a temperature that is predicted adaptively during contrastive training, so bands with different signal statistics are balanced automatically. On the ADFTD cohort under a strict leave-one-subject-out protocol, Delta2Gamma separates Alzheimer's disease from cognitively normal controls with 92.4\% accuracy. This exceeds both supervised backbones and recent dedicated EEG methods.

Decoupling Parcellation from Classification: Systematic Benchmark of Fast Brain Segmentation Methods for Alzheimer's Disease Detection

Brain parcellation and classification are typically evaluated in isolation, yet downstream AD detection performance depends on their interaction. We decouple these components and systematically benchmark fast deep learning parcellation methods (SynthSeg+, OpenMAP-T1) against the FreeSurfer (FS-HV) clinical baseline through down- stream AD classification on OASIS-1. Our factorial design evaluates three parcellation methods, two volumetry strategies (hard vs. soft), and four classifier paradigms (clinical thresholds, supervised feedforward networks, ensemble methods, and foundation models with zero/few-shot prompting), with all results quantified using BCa Bootstrap 95% confidence intervals.

Data-driven techniques for translational neuroscience and personalized neuro-health

Neurodegenexrative diseases such as Alzheimer's disease and Parkinson's disease are diagnosed most reliably only after substantial, often irreversible, neuronal loss has already occurred, creating an urgent need for quantitative tools that can detect subtle, early, and individual-specific brain changes from neuroimaging data. This review surveys a broad and rapidly evolving toolkit of data-driven techniques for translational neuroscience and personalized neuro-health, organized around four complementary methodological pillars. Throughout, we emphasize how these methodologically diverse approaches converge on a common translational goal: personalized, mechanistically grounded, and clinically actionable models of individual brain health, and we close by discussing the principal open statistical, computational, and clinical challenges that remain.

Emergence of Transfer Learning towards Specific Identification of Alzheimer's Disease A Prospective Approach

Worldwide, millions of senior citizens are suffering from Alzheimer disease abbreviated as AD, a well- versed form of dementia. AD is featured by amnesia, intellectual disability, and difficulty with consciousness. DL and ML models are undoubtedly explored to identify AD related patterns on large dimensional neuroimaging data but they need global optimization and are suffering from overfitting issue that might yield dissatisfactory result in testing data set. DL overcomes the issue by convolution of input image with kernel but any sudden change in the MRI image or human manipulation, limited pre- processing of the images can mislead CNN in achieving highly accurate detection. Transfer Learning (TL) has proved itself in AD diagnosis by utilizing pre-trained models on large data sets to guide novice model in a new neuroimaging dataset. This review provides an inclusive glimpse of TL implication in classification, identification including the conversion of AD. Keeping in view, we have assessed the strengths and limitations of TL in improvising diagnostic accuracy even with limited data. The uniqueness of the present review is the incorporation of explainable AI in TL based AD diagnosis system. Finally, it can be claimed that the review will guide the new re-searchers in the area of TL induced neurodegenerative disease detection.

A comparison of CNN architectures for Alzheimer's disease detection in single-view MRI scans

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.

Parcel2Progression: An Anatomy-aware Longitudinal Framework for Alzheimer's Disease Diagnosis

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.

$\texttt{DisMorph}$: learning to disentangle technical distortions from true biological change

Longitudinal MRI enables sensitive measurement of structural brain change for studying aging and neurodegenerative disease. Deformable image registration is a key tool for estimating such change by computing a dense deformation that captures geometric differences between longitudinal scans. However, MRI scanners introduce geometric distortions that vary across acquisition systems and protocols, such as gradient non-linearity (GNL) distortion. Existing registration methods estimate a single field that conflates biological and technical effects, potentially biasing downstream morphometric measurements if distortions remain (partially) uncorrected. We propose $\texttt{DisMorph}$, a registration framework trained entirely on synthetic data that explicitly decomposes longitudinal deformation into technical and anatomical transforms. It predicts two dense deformations, each encoding one effect. During training, a novel generative model synthesizes both effects separately to provide disentanglement supervision, while domain randomization promotes generalization across imaging protocols. We evaluate our method in three complementary settings. On simulated data with known ground truth, our method detects anatomical change more accurately and consistently than conventional registration. On real image pairs that differ only by GNL distortion, our method assigns most geometric change to the distortion field, demonstrating specificity in the absence of anatomical change. On longitudinal Alzheimer's disease (AD) pairs, our method detects anatomical change in AD-related brain structures while identifying residual distortion left after standard correction. By disentangling MRI-induced distortion from biological change in the longitudinal deformation, our method paves the way for more accurate longitudinal morphometry in clinical settings where maintaining acquisition consistency is challenging.

LSEAD: A Privacy-Preserving LLM-Based Speech Analysis Framework for Early Alzheimer's Disease Screening

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.

When Is a Conformal Guarantee Fair? Auditing Silent Subgroup Under-Coverage in Alzheimer's Disease Longitudinal Prediction

Longitudinal prediction of Alzheimer's disease biomarkers increasingly informs clinical decisions, and a forecast is only useful if it also reports how much to trust it. Conformal prediction supplies this by wrapping any forecaster in a prediction band with a finite-sample coverage guarantee under exchangeability. However, standard population-level conformal prediction guarantees only marginal coverage and may mask substantial under-coverage within clinically important subgroups. We introduce a general mechanism-driven framework for auditing and repairing such subgroup under-coverage. Across two cohorts (ADNI, OASIS-3), two base forecasters, and nine attributes spanning genetic risk, demographics, and clinical severity, we find that population-level bands under-cover high-risk subgroups in 57 of 68 audited combinations, despite achieving nominal marginal coverage. We trace these failures to two mechanisms: (A) \emph{rarity}, where a group-conditional band calibrated on only $n$ patients covers at most $k/(n+1)$; and (B) \emph{tail-heaviness}, where a population-wide band is too narrow for a heavy-tailed subgroup and additional data cannot close the gap. Under-coverage falls disproportionately on patients with high genetic risk and disease severity (6.1 pp mean deficit, 95\% CI [3.3, 8.9]), while demographic groups remain at the target level on average (0.0 pp, CI [$-1.9$, 1.7]). We pair each mechanism with a corresponding conformal correction: cross-conformal pooling for rarity, per-subgroup calibration for tail-heaviness, and a coverage-safe marginal floor when both arise. Together, these corrections restore target coverage for nearly every high-risk subgroup across both cohorts and forecasters.

Activation-Guided Neuron Intervention to Induce Alzheimer's-Related Computational Language Phenotypes in a Large Language Model

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.

PatTree: a novel approach for automated creation of multimodal, graph-based patient representations for medical classification tasks

Access to holistic, multimodal data improves the performance of Artificial Intelligence (AI) in medical classification tasks compared to utilizing single modalities or data sources. However, the inherent heterogeneity and complexity of clinical real-world data pose significant challenges to structured data analysis and AI application. This heterogeneity includes missing values, multiple time points, diverse modalities, and inconsistent formats and semantics. Data harmonization prior to data integration tackles this challenge but remains resource-intensive and error-prone, limiting the scalability and reproducibility of holistic, AI-driven decision support on clinical real-world data. We therefore propose PatTree, a graph-based, holistic representation of patients that can be derived from real-world clinical data through the automated structuring of multimodal clinical data. PatTree enables early-stage data integration without relying on pre-standardized inputs. While representing heterogeneous clinical data within a unified knowledge graph, PatTree preserves the semantic relationships between data elements across modalities and data sources, facilitating interoperability and machine-interpretable data access. Using a subset of the ADNI-1 cohort (n = 763), we demonstrate that classification of patients is directly feasible on PatTree reaching state-of-the-art classification performance. In the three-class classification task distinguishing Alzheimer's disease, mild cognitive impairment, and cognitively normal individuals, we achieve a balanced accuracy of 98.5% and an F$_1$ score of 0.987 on the held-out test set. Our results show that assumption-free, automated structuring of multimodal medical data can serve as a scalable foundation for clinical AI pipelines bypassing tedious data preparation and standardization.

A Neurosymbolic Approach for Explainable Early Diagnosis of Alzheimer's Disease

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.

MPP-GNN: Subject-Adaptive Community Detection for fMRI-Based Alzheimer's Disease Classification

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.

An Attention-Based Framework for Alzheimers Disease Classification Using Resting-State fMRI

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.

Disentangling Acoustic Cues in Alzheimer's Pathology and Perception: The Roles of Language and Gender

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.

Calibrated Alzheimer's Conversion Risk in Mild Cognitive Impairment: Persistent Homology of Clinical Trajectories with Conformal Guarantees

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.

Imputation-free transformer learning enables robust Alzheimer's disease prediction and calibrated uncertainty quantification across heterogeneous clinical cohorts

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.

Transcript-Free Lightweight Detection of Alzheimer's Disease from Spontaneous Speech Using Handcrafted MFCC-Dominant Acoustic Biomarkers

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.

CASL-VAE: Learning Structured Latent Variables from Unpaired Data for Semi-supervised Clustering and Paired Sample Generation

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.

MVMGNN;Multi-View Masked Graph Neural Network for Alzheimer's Disease Diagnosis using Structural MRI

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

AT-Attn: Temporal-Aware Cross-Attention for Longitudinal Multimodal Alzheimer's Disease Diagnosis

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.

Predicting Early Stages Of Alzheimer's Disease And Identifying Key Biomarkers Using Deep Artificial Neural Network And Ensemble Of Machine Learning Methodologies

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.