AI-based characterization of Alzheimer's disease phenotypes from population-scale single-cell data

The complexity of Alzheimer's disease (AD) manifests in diverse clinical phenotypes, including cognitive impairment and neuropsychiatric symptoms. However, the etiology of these phenotypes remains elusive. To address this, the PsychAD project generated a population-level single-nucleus RNA sequencing dataset comprising over 6 million nuclei from the prefrontal cortex of >1,000 individual brains, covering a variety of disease phenotypes. Here, leveraging this dataset, we developed a computational framework, called Phenotype Associated Single Cell encoder (PASCode), to score single-cell phenotype associations, and identified ∼1.5 million phenotype-associated cells (PACs) from 584 donors with AD-related phenotypes. PASCode ensembles multiple statistical methods into a graph neural model for robust scoring. Comparing PACs within 27 brain cell subclasses, we prioritized cell subpopulations and their expressed genes for various AD phenotypes. For instance, we identified microglia subpopulations implicated in AD pathology; reactive astrocyte subtypes with altered neuroprotective and neurotoxic gene expression that likely confer cognitive resilience; and enhanced excitatory/inhibitory imbalance and mitochondrial dysfunction in cognitively impaired AD donors. We also identified many PACs for multiple phenotypes, including the astrocytes between AD and depression showing specific gene expression patterns such as inflammation and endoplasmic reticulum stress pathways. These prioritized subpopulations, genes and pathways potentially offer valuable insights for precision diagnostic and therapeutic development. We also validated our findings in external population-scale datasets including AD and major depressive disorder, compiled an AD-phenotypic single-cell atlas and delivered the framework as an open-source tool with pre-trained models and a web application for community use.