Olfactory radiomics signatures link pTau217 to cognitive impairment in probable Alzheimer's disease: a multi-cohort machine learning study.
Ben Chen, Pengbo Gao, Huanmin Liu, Danyan Xu, Qiang Wang, Mingfeng Yang, Haoye Tan, Zhidai Xiao, Shihan Tian, Zihan Wang, Youxuan Zheng, Xiaomin Zheng, Shuang Liang, Qin Liu, Jiafu Li, Xiaomei Zhong, Yuping Ning
BACKGROUND: Alzheimer's disease (AD) diagnosis remains challenging because current molecular biomarkers, though sensitive, lack spatial specificity. Radiomics offers a promising alternative by quantifying subtle microstructural alterations from routine MRI that are invisible to traditional volumetric analyses. Given that olfactory-related regions are preferentially affected in AD with olfactory dysfunction preceding cognitive decline, this study aimed to develop and validate radiomics signatures from these regions as imaging biomarkers linking molecular pathology to clinical phenotypes. METHODS: Radiomics models were developed and validated across 834 participants from three independent cohorts: in-house cohort of 278 participants (122 AD, 156 cognitively unimpaired controls) ADNI and OASIS validation (each with RESULTS: The hippocampus-amygdala radiomics signatures achieved superior diagnostic performance across all six algorithms and three cohorts (AUC: 0.86–0.92, accuracy: 0.81–0.88). These signatures significantly outperformed those from piriform cortex, entorhinal cortex, and orbitofrontal cortex. Radiomics models demonstrated marginally higher AUC values and superior sensitivity (0.776–0.869 vs 0.505–0.811) compared to volumetric models. Hierarchical regression analyses revealed that radiomics features showed significant incremental contributions in 75.7% of analyses compared to only 12.5% for volumetric features in the all-participants group (6.1-fold advantage), with substantially higher mean incremental variance explained (ΔAdjR CONCLUSIONS: Radiomics signatures from olfactory-related regions, particularly the hippocampus-amygdala complex, represent non-invasive associative imaging biomarkers statistically linking tau pathology and olfactory deficits to cognitive impairment. These findings establish accessible imaging correlates that complement blood tests for enhanced diagnosis and patient stratification in AD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02053-0.
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