# Toward Personalized Digital Twins for Cognitive Decline Assessment: A Multimodal, Uncertainty-Aware Framework

arXiv: https://arxiv.org/abs/2604.27217 · HTML: https://mlsanity.com/paper/2604.27217/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 1 of its 21 references that are in the map.
- First posted on arXiv 29 Apr 2026.

## Builds on (most cited first, 1 of 1)

- [Modeling Disease Progression in Mild Cognitive Impairment and Alzheimer's Disease with Digital Twins](https://mlsanity.com/paper/2012.13455/) (2020)

## Abstract (arXiv)

Cognitive decline is highly heterogeneous across individuals, which complicates prognosis, trial design, and treatment planning. We present the Personalized Cognitive Decline Assessment Digital Twin (PCD-DT), a multimodal and uncertainty-aware framework for modeling patient-specific disease trajectories from sparse, noisy, and irregular longitudinal data. The framework combines three methodological components: (1) latent state-space models for individualized temporal dynamics, (2) multimodal fusion for clinical, biomarker, and imaging features, and (3) uncertainty-aware validation and adaptive updating for robust digital twin operation. We also outline how conditional generative models can support data augmentation and stress testing for underrepresented progression patterns. As a preliminary feasibility study, we analyze longitudinal TADPOLE trajectories and show clear separation between cognitively normal and Alzheimer's disease cohorts in ADAS13, ventricle volume, and hippocampal volume over five years. We further conduct a multimodal next-visit prediction ablation using an LSTM sequence model on 3{,}003 visit-pair sequences derived from TADPOLE, where the combined cognitive plus MRI configuration achieves the lowest standardized RMSE for both ADAS13 (0.4419) and ventricle volume (0.5842), outperforming a Last Observation Carried Forward baseline. A Bayesian tensor modeling component for high-dimensional imaging fusion is also discussed. These results support the feasibility of the proposed architecture while also highlighting the need for stronger uncertainty calibration and longer-horizon predictive evaluation. The PCD-DT framework provides a principled starting point for personalized in silico modeling in neurodegenerative disease. This work positions PCD-DT as a foundational step toward clinically deployable, uncertainty-aware digital twin systems.