# A Two-Stage Framework for Early Detection and Subtype Identification of Alzheimer’s Disease Through Multimodal Biomarker Extraction and Improved GCN

## TL;DR

This paper introduces a two-stage framework combining MRI, PET, and transcriptomic data to detect Alzheimer's disease early and identify subtypes of mild cognitive impairment.

## Contribution

The novel MFEAA-GCNSASE framework improves early AD detection and subtype identification through multimodal biomarker extraction and enhanced GCN with self-attention.

## Key findings

- The framework identified robust biomarkers like the Left Hippocampus and genes SLC25A5 and GABARAP.
- GCNSASE achieved state-of-the-art performance with mean AUC values from 0.946 to 0.961.
- Clustering analysis revealed two MCI subtypes with distinct molecular pathways and conversion risks to AD.

## Abstract

Background: Imaging-transcriptomic analysis, through the integration of multimodal magnetic resonance imaging (MRI) and transcriptomic data, provides complementary structural, functional, and molecular information that is crucial for the early detection and mechanistic exploration of Alzheimer’s disease (AD). However, effectively extracting features from heterogeneous multimodal data and capturing the associations between microscopic molecular variations and macroscopic brain alterations remain key challenges. Recent advances in deep learning and multimodal integration have enhanced the ability to model nonlinear cross-modal relationships, enabling more accurate identification of imaging-transcriptomic biomarkers and subtypes. Developing robust multimodal frameworks is therefore essential for early AD detection, subtype identification, and advancing precision medicine in neurodegenerative diseases. Methods: In this study, a two-stage method of multimodal Feature Extraction based on Association Analysis and Graph Convolutional Network with Self-Attention and Self-Expression framework (MFEAA-GCNSASE) for early diagnosis of AD and effective identification of subtypes of MCI with different progression to AD is proposed. In the first stage, the MFEAA model is applied to integrate multiple association analysis methods on sMRI, PET, and transcriptomic data to identify key multimodal biomarkers for AD and mild cognitive impairment (MCI). In the second stage, the GCNSASE model enhances classification accuracy between AD and MCI patients through self-attention and self-expression layers. Additionally, unsupervised clustering was performed on MCI samples using top multimodal biomarkers to explore subtype heterogeneity and conversion risk. Reliable MCI subtypes were also identified through a consensus clustering approach. Results: The proposed algorithm integrates sMRI, PET, and transcriptomic data, identifying robust biomarkers including the Left Hippocampus, Left Angular Gyrus, and key genes such as SLC25A5 and GABARAP. To ensure statistical robustness given the extreme class imbalance, we employed a rigorous repeated stratified cross-validation (RSCV) framework. GCNSASE achieved state-of-the-art discrimination performance with mean AUC values ranging from 0.946 to 0.961 across feature subsets (10–50%), significantly outperforming MOGONET (mean AUC: 0.844–0.875, p < 0.001) and conventional machine learning models with tighter 95% confidence intervals, indicating superior stability despite the limited AD sample size. Clustering analysis revealed two distinct MCI subtypes with divergent molecular landscapes: Subtype A was enriched in energy metabolism and cellular maintenance pathways, whereas Subtype B was enriched in neuroinflammatory and aberrant signaling pathways. Notably, the majority of MCI patients who subsequently converted to AD were concentrated in the immune-inflammatory Subtype B. These findings highlight that neuroinflammation coupled with bioenergetic failure constitutes a critical mechanism driving the conversion from MCI to AD. Conclusions: The proposed methods not only provide the key multimodal biomarkers and enhance the accuracy of the classification model for early AD diagnosis but also identify biologically and clinically meaningful MCI subtypes with distinct molecular signatures and conversion risks. Exploring these associated multimodal biomarkers and MCI subtypes is of great significance, as they help elucidate the heterogeneous mechanisms underlying AD onset and progression, enable the identification of high-risk individuals likely to convert to AD, and provide a foundation for targeted therapeutic strategies and individualized clinical management. These findings have important implications for understanding disease heterogeneity, discovering potential intervention targets, and advancing precision medicine in neurodegenerative diseases.