Autoencoder to Identify Sex-Specific Sub-phenotypes in Alzheimer's Disease Progression Using Longitudinal Electronic Health Records

Alzheimer's Disease (AD) is a complex neurodegenerative disorder significantly influenced by sex differences, with approximately two-thirds of AD patients being women. Characterizing the sex-specific AD progression and identifying its progression trajectory is a crucial step to developing effective risk stratification and prevention strategies. In this study, we developed an autoencoder to uncover sex-specific sub-phenotypes in AD progression leveraging longitudinal electronic health record (EHR) data from OneFlorida+ Clinical Research Consortium. Specifically, we first constructed temporal patient representation using longitudinal EHRs from sex-stratified AD cohort. We used a long short-term memory (LSTM)-based autoencoder to extract and generate latent representation embeddings from sequential clinical records of patients. We then applied hierarchical agglomerative clustering to the learned representations, grouping patients based on their progression sub-phenotypes. The experimental results show that we successfully identified five primary sex-based AD sub-phenotypes with corresponding progression pathways with high confidence. These sex-specific sub-phenotypes not only illustrated distinct AD progression patterns but also revealed differences in clinical characteristics and comorbidities between females and males in AD development. These findings could provide valuable insights for advancing personalized AD intervention and treatment strategies.