Alzheimer's Disease Progression Prediction

Neuropsychiatric symptoms (NPS) such as depression and apathy are common in Alzheimer's disease (AD) and often precede cognitive decline. NPS assessments hold promise as early detection markers due to their correlation with disease progression and their non-invasive nature. Yet current tools cannot distinguish whether NPS are part of aging or early signs of AD, limiting their utility. We present a deep learning-based normative modelling framework to identify atypical NPS burden from structural MRI. A 3D convolutional neural network was trained on cognitively stable participants from the Alzheimer's Disease Neuroimaging Initiative, learning the mapping between brain anatomy and Neuropsychiatric Inventory Questionnaire (NPIQ) scores. Deviations between predicted and observed scores defined the Divergence from NPIQ scores (DNPI). Higher DNPI was associated with future AD conversion (adjusted OR=2.5; p < 0.01) and achieved predictive accuracy comparable to cerebrospinal fluid AB42 (AUC=0.74 vs 0.75). Our approach supports scalable, non-invasive strategies for early AD detection.

Predicting whether someone with mild cognitive impairment (MCI) will progress to Alzheimer's disease (AD) is crucial in the early stages of neurodegeneration. This uncertainty limits enrollment in clinical trials and delays urgent treatment. The Boundary Sharpness Coefficient (BSC) measures how well-defined the gray-white matter boundary looks on structural MRI. This study measures how BSC changes over time, namely, how fast the boundary degrades each year works much better than looking at a single baseline scan for predicting MCI-to-AD conversion. This study analyzed 1,824 T1-weighted MRI scans from 450 ADNI subjects (95 converters, 355 stable; mean follow-up: 4.84 years). BSC voxel-wise maps were computed using tissue segmentation at the gray-white matter cortical ribbon. Previous studies have used CNN and RNN models that reached 96.0% accuracy for AD classification and 84.2% for MCI conversion, but those approaches disregard specific regions within the brain. This study focused specifically on the gray-white matter interface. The approach uses temporal slope features capturing boundary degradation rates, feeding them into Random Survival Forest, a non-parametric ensemble method for right-censored survival data. The Random Survival Forest trained on BSC slopes achieved a test C-index of 0.63, a 163% improvement over baseline parametric models (test C-index: 0.24). Structural MRI costs a fraction of PET imaging ($800--$1,500 vs. $5,000--$7,000) and does not require CSF collection. These temporal biomarkers could help with patient-centered safety screening as well as risk assessment.

Longitudinal neuroimaging is essential for modeling disease progression in Alzheimer's disease (AD), yet irregular sampling and missing visits pose substantial challenges for learning reliable temporal representations. To address this challenge, we propose SDE-HGNN, a stochastic differential equation (SDE)-driven spatio-temporal hypergraph neural network for irregular longitudinal fMRI connectome modeling. The framework first employs an SDE-based reconstruction module to recover continuous latent trajectories from irregular observations. Based on these reconstructed representations, dynamic hypergraphs are constructed to capture higher-order interactions among brain regions over time. To further model temporal evolution, hypergraph convolution parameters evolve through SDE-controlled recurrent dynamics conditioned on inter-visit intervals, enabling disease-stage-adaptive connectivity modeling. We also incorporate a sparsity-based importance learning mechanism to identify salient brain regions and discriminative connectivity patterns. Extensive experiments on the OASIS-3 and ADNI cohorts demonstrate consistent improvements over state-of-the-art graph and hypergraph baselines in AD progression prediction. The source code is available at https://anonymous.4open.science/r/SDE-HGNN-017F.

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

Disease progression modeling provides a robust framework to identify long-term disease trajectories from short-term biomarker data. It is a valuable tool to gain a deeper understanding of diseases with a long disease trajectory, such as Alzheimer's disease. A key limitation of most disease progression models is that they are specific to a single data type (e.g., continuous data), thereby limiting their applicability to heterogeneous, real-world datasets. To address this limitation, we propose the Mixed Events model, a novel disease progression model that handles both discrete and continuous data types. This model is implemented within the Subtype and Stage Inference (SuStaIn) framework, resulting in Mixed-SuStaIn, enabling subtype and progression modeling. We demonstrate the effectiveness of Mixed-SuStaIn through simulation experiments and real-world data from the Alzheimer's Disease Neuroimaging Initiative, showing that it performs well on mixed datasets. The code is available at: https://github.com/ucl-pond/pySuStaIn.

Evaluating personalized, sequential treatment strategies for Alzheimer's disease (AD) using clinical trials is often impractical due to long disease horizons and substantial inter-patient heterogeneity. To address these constraints, we present the Alzheimer's Learning Platform for Adaptive Care Agents (ALPACA), an open-source, Gym-compatible reinforcement learning (RL) environment for systematically exploring personalized treatment strategies using existing therapies. ALPACA is powered by the Continuous Action-conditioned State Transitions (CAST) model trained on longitudinal trajectories from the Alzheimer's Disease Neuroimaging Initiative (ADNI), enabling medication-conditioned simulation of disease progression under alternative treatment decisions. We show that CAST autoregressively generates realistic medication-conditioned trajectories and that RL policies trained in ALPACA outperform no-treatment and behavior-cloned clinician baselines on memory-related outcomes. Interpretability analyses further indicated that the learned policies relied on clinically meaningful patient features when selecting actions. Overall, ALPACA provides a reusable in silico testbed for studying individualized sequential treatment decision-making for AD.

Accurately modeling longitudinal brain MRI progression is crucial for understanding neurodegenerative diseases and predicting individualized structural changes. Existing state-of-the-art approaches, such as Brain Latent Progression (BrLP), often use multi-stage training pipelines with auxiliary conditioning modules but suffer from architectural complexity, suboptimal use of conditional clinical covariates, and limited guarantees of anatomical consistency. We propose Anatomically Guided Latent Diffusion Model (AG-LDM), a segmentation-guided framework that enforces anatomically consistent progression while substantially simplifying the training pipeline. AG-LDM conditions latent diffusion by directly fusing baseline anatomy, noisy follow-up states, and clinical covariates at the input level, a strategy that avoids auxiliary control networks by learning a unified, end-to-end model that represents both anatomy and progression. A lightweight 3D tissue segmentation model (WarpSeg) provides explicit anatomical supervision during both autoencoder fine-tuning and diffusion model training, ensuring consistent brain tissue boundaries and morphometric fidelity. Experiments on 31,713 ADNI longitudinal pairs and zero-shot evaluation on OASIS-3 demonstrate that AG-LDM matches or surpasses more complex diffusion models, achieving highly competitive image quality and 15-20% reduction in volumetric errors in generated images. AG-LDM also exhibits markedly stronger utilization of temporal and clinical covariates (3.5-31.5x higher covariate sensitivity than BrLP) and generates biologically plausible counterfactual trajectories, accurately capturing hallmarks of Alzheimer's progression such as limbic atrophy and ventricular expansion. These results highlight AG-LDM as an efficient, anatomically grounded framework for reliable brain MRI progression modeling.

While Large Language Models (LLMs) have shown strong performance on clinical text understanding, they struggle with longitudinal prediction tasks such as dementia prognosis, which require reasoning over complex, non-monotonic symptom trajectories across multiple visits. Standard supervised training lacks explicit annotations for symptom evolution, while direct Reinforcement Learning (RL) is hindered by sparse binary rewards. To address this challenge, we introduce Dementia-R1, an RL-based framework for longitudinal dementia prognosis from unstructured clinical notes. Our approach adopts a Cold-Start RL strategy that pre-trains the model to predict verifiable clinical indices extracted from patient histories, enhancing the capability to reason about disease progression before determining the final clinical status. Extensive experiments show that Dementia-R1 achieves the best overall performance on the AMC real-world unstructured cohort, reaching an AUROC of 84.02% and outperforming models up to 10x larger. The framework also generalizes to Parkinson's disease dementia prediction in an independent hospital cohort, achieving an AUROC of 78.37%. On the ADNI benchmark, our 7B model attains the highest AUROC among all LLM baselines at 83.17%, demonstrating strong longitudinal reasoning over fluctuating cognitive trajectories. Code is available at https://anonymous.4open.science/r/dementiar1-CDB5.

Generative modeling frameworks have emerged as an effective approach to capture high-dimensional image distributions from large datasets without requiring domain-specific knowledge, a capability essential for disease progression modeling. Recent generative approaches have attempted to capture progression by mapping images to a latent space and guiding representations to generate follow-up images from previous time points. However, these methods impose constraints on distribution learning, resulting in latent spaces with limited controllability for generating follow-up images without paired subject-specific longitudinal guidance. In order to enable controlled movements in the latent representational space and generate progression images from a previous time-point image without subject-specific guidance, we introduce a conditionable Diffusion Auto-encoder framework that forms a compact latent space capturing high-level semantics and providing means to control generation. Our approach leverages this latent space to condition and apply controlled shifts to the representations of previous time-point images by isolating progression and subject identity information for generating follow-up images. The shifts are implicitly guided by correlating with progression attributes and constraining to Alzheimer's disease specific regions, without paired longitudinal guidance. We validate the generations through image quality metrics, volumetric progression analysis, and downstream tasks in Alzheimer's disease datasets from different sources. This demonstrates the effectiveness of our approach for Alzheimer's progression modeling and longitudinal image generation.