Tian Han ¹ Yunhua Peng ¹ Ying Du ² Yunbo Li ² Ying Wang ¹ Wentong Sun ¹ Lanxin Cui ¹ Qinke Peng ^1*

• ¹ Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
• ² Tangdu Hospital, Air Force Medical University, Xi'an, Shaanxi Province, China

Because Alzheimer's disease (AD) has significant heterogeneity in encephalatrophy and clinical manifestations, AD research faces two critical challenges: eliminating the impact of natural aging and extracting valuable clinical data for patients with AD. This study attempted to address these challenges by developing a novel machine-learning model called tensorized contrastive principal component analysis (T-cPCA). The objectives of this study were to predict AD progression and identify clinical subtypes while minimizing the influence of natural aging. We leveraged a clinical variable space of 872 features, including almost all AD clinical examinations, which is the most comprehensive AD feature description in current research. T-cPCA yielded the highest accuracy in predicting AD progression by effectively minimizing the confounding effects of natural aging. Moreover, the representative features and pathogenic circuits of the four primary AD clinical subtypes were discovered. Confirmed by clinical doctors in Tangdu Hospital, the plaques (18F-AV45) distribution of typical patients in the four clinical subtypes are consistent with representative brain regions found in four AD subtypes, which further offers novel insights into the underlying mechanisms of AD pathogenesis.