# Forecasting Medium-Horizon Alzheimer's Disease Progression: Residual Gap-Aware Transformers for 24-Month CDR-SB Change from ADNI Clinical and Biomarker Histories

arXiv: https://arxiv.org/abs/2605.16319 · HTML: https://mlsanity.com/paper/2605.16319/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 6 of its 35 references that are in the map.
- First posted on arXiv 4 May 2026.

## Builds on (most cited first, 6 of 6)

- [Attention Is All You Need](https://mlsanity.com/paper/1706.03762/) (2017)
- [Recurrent Neural Networks for Multivariate Time Series with Missing Values](https://mlsanity.com/paper/1606.01865/) (2016)
- [A Transformer-based Framework for Multivariate Time Series Representation Learning](https://mlsanity.com/paper/2010.02803/) (2020)
- [Self-Supervised Transformer for Sparse and Irregularly Sampled Multivariate Clinical Time-Series](https://mlsanity.com/paper/2107.14293/) (2021)
- [Machine learning for modeling the progression of Alzheimer disease dementia using clinical data: a systematic literature review](https://mlsanity.com/paper/2108.04174/) (2021)
- [TA-RNN: an Attention-based Time-aware Recurrent Neural Network Architecture for Electronic Health Records](https://mlsanity.com/paper/2401.14694/) (2024)

## Abstract (arXiv)

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.