# AD-DAE: Alzheimer's Disease Progression Modeling with Unpaired Longitudinal MRI using Diffusion Auto-Encoders

arXiv: https://arxiv.org/abs/2511.05934 · HTML: https://mlsanity.com/paper/2511.05934/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 26 of its 47 references that are in the map.
- First posted on arXiv 8 Nov 2025.

## Builds on (most cited first, 26 of 26)

- [Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2006.11239/) (2020)
- [Denoising Diffusion Implicit Models](https://mlsanity.com/paper/2010.02502/) (2020)
- [Diffusion Models Beat GANs on Image Synthesis](https://mlsanity.com/paper/2105.05233/) (2021)
- [Improved Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2102.09672/) (2021)
- [Aggregated Residual Transformations for Deep Neural Networks](https://mlsanity.com/paper/1611.05431/) (2016)
- [Diffusion Autoencoders: Toward a Meaningful and Decodable Representation](https://mlsanity.com/paper/2111.15640/) (2021)
- [Age Progression/Regression by Conditional Adversarial Autoencoder](https://mlsanity.com/paper/1702.08423/) (2017)
- [SynthSeg: Segmentation of brain MRI scans of any contrast and resolution without retraining](https://mlsanity.com/paper/2107.09559/) (2021)
- [Diffusion Model-Based Image Editing: A Survey](https://mlsanity.com/paper/2402.17525/) (2024)
- [SSR-Encoder: Encoding Selective Subject Representation for Subject-Driven Generation](https://mlsanity.com/paper/2312.16272/) (2023)
- [SODA: Bottleneck Diffusion Models for Representation Learning](https://mlsanity.com/paper/2311.17901/) (2023)
- [Diffusion Deformable Model for 4D Temporal Medical Image Generation](https://mlsanity.com/paper/2206.13295/) (2022)
- [DiffuseMorph: Unsupervised Deformable Image Registration Using Diffusion Model](https://mlsanity.com/paper/2112.05149/) (2021)
- [SADM: Sequence-Aware Diffusion Model for Longitudinal Medical Image Generation](https://mlsanity.com/paper/2212.08228/) (2022)
- [Unsupervised Representation Learning from Pre-trained Diffusion Probabilistic Models](https://mlsanity.com/paper/2212.12990/) (2022)
- [NoiseCLR: A Contrastive Learning Approach for Unsupervised Discovery of Interpretable Directions in Diffusion Models](https://mlsanity.com/paper/2312.05390/) (2023)
- [Learning to synthesise the ageing brain without longitudinal data](https://mlsanity.com/paper/1912.02620/) (2019)
- [UVCGAN: UNet Vision Transformer cycle-consistent GAN for unpaired image-to-image translation](https://mlsanity.com/paper/2203.02557/) (2022)
- [Equitable modelling of brain imaging by counterfactual augmentation with morphologically constrained 3D deep generative models](https://mlsanity.com/paper/2111.14923/) (2021)
- [Exploring Diffusion Time-steps for Unsupervised Representation Learning](https://mlsanity.com/paper/2401.11430/) (2024)
- [Enhancing Spatiotemporal Disease Progression Models via Latent Diffusion and Prior Knowledge](https://mlsanity.com/paper/2405.03328/) (2024)
- [Degenerative Adversarial NeuroImage Nets for Brain Scan Simulations: Application in Ageing and Dementia](https://mlsanity.com/paper/1912.01526/) (2019)
- [Hierarchical Diffusion Autoencoders and Disentangled Image Manipulation](https://mlsanity.com/paper/2304.11829/) (2023)
- [Pluralistic Aging Diffusion Autoencoder](https://mlsanity.com/paper/2303.11086/) (2023)
- [Individualized multi-horizon MRI trajectory prediction for Alzheimer's Disease](https://mlsanity.com/paper/2408.02018/) (2024)
- [PosDiffAE: Position-aware Diffusion Auto-encoder For High-Resolution Brain Tissue Classification Incorporating Artifact Restoration](https://mlsanity.com/paper/2507.02405/) (2025)

## Abstract (arXiv)

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.