Molecular subtyping of Alzheimer's disease using RNA sequencing data reveals novel mechanisms and targets

Alzheimer's disease (AD), the most common form of dementia, is recognized as a heterogeneous disease with diverse pathophysiologic mechanisms. In this study, we interrogate the molecular heterogeneity of AD by analyzing 1543 transcriptomes across five brain regions in two AD cohorts using an integrative network approach. We identify three major molecular subtypes of AD corresponding to different combinations of multiple dysregulated pathways, such as susceptibility to tau-mediated neurodegeneration, amyloid-beta neuroinflammation, synaptic signaling, immune activity, mitochondria organization, and myelination. Multiscale network analysis reveals subtype-specific drivers such as GABRB2, LRP10, MSN, PLP1, and ATP6V1A. We further demonstrate that variations between existing AD mouse models recapitulate a certain degree of subtype heterogeneity, which may partially explain why a vast majority of drugs that succeeded in specific mouse models do not align with generalized human trials across all AD subtypes. Therefore, subtyping patients with AD is a critical step toward precision medicine for this devastating disease.

Automated summary

This study identified three major molecular subtypes of Alzheimer's disease (AD) and specific driver genes through analyzing transcriptomes from multiple brain regions. The research also demonstrated that existing AD mouse models reflect some degree of subtype heterogeneity, possibly explaining the lack of alignment between successful drugs in specific mouse models and generalized human trials across all AD subtypes. Subtyping patients with AD is considered a critical step towards precision medicine for this devastating disease.