Unsupervised Deep Learning of Electronic Health Records to Characterize Heterogeneity Across Alzheimer Disease and Related Dementias: Cross-Sectional Study.

Background: Alzheimer disease and related dementias (ADRD) exhibit prominent heterogeneity. Identifying clinically meaningful ADRD subtypes is essential for tailoring treatments to specific patient phenotypes.

Objective: We aimed to use unsupervised learning techniques on electronic health records (EHRs) from memory clinic patients to identify ADRD subtypes.

Methods: We used pretrained embeddings of non-ADRD diagnosis codes (International Classification of Diseases, Ninth Revision) and large language model (LLM)-derived embeddings of clinical notes from patient EHRs. Hierarchical clustering of these embeddings was used to identify ADRD subtypes. Clusters were characterized regarding their demographic and clinical features.

Results: We analyzed a cohort of 3454 patients with ADRD from a memory clinic at Massachusetts General Hospital, each with a specialist diagnosis. Clustering pretrained embeddings of the non-ADRD diagnosis codes in patient EHRs revealed the following 3 patient subtypes: one with skin conditions, another with psychiatric disorders and an earlier age of onset, and a third with diabetes complications. Similarly, using LLM-derived embeddings of clinical notes, we identified 3 subtypes of patients as follows: one with psychiatric manifestations and higher prevalence of female participants (prevalence ratio: 1.59), another with cardiovascular and motor problems and higher prevalence of male participants (prevalence ratio: 1.75), and a third one with geriatric health disorders. Notably, we observed significant overlap between clusters from both data modalities (χ=89.4; P<.001).

Conclusions: By integrating International Classification of Diseases, Ninth Revision codes and LLM-derived embeddings, our analysis delineated 2 distinct ADRD subtypes with sex-specific comorbid and clinical presentations, offering insights for potential precision medicine approaches.