Plasma proteomics reveals continuous molecular heterogeneity rather than discrete subtypes in Alzheimer's disease

Alzheimer's disease is clinically and biologically heterogeneous. We asked whether plasma proteomics separates patients into discrete molecular subtypes or instead reflects continuous biological variation. We studied 5,895 Global Neurodegeneration Proteomics Consortium (GNPC) participants with Alzheimer's disease or mild cognitive impairment using protein coexpression networks, clustering, and continuous molecular-axis analysis. External analyses used Stanford Alzheimer's Disease Research Center (ADRC) biomarker/imaging data and UK Biobank proteomics.Four continuous axes captured 81.5% of module-level proteomic variation. Although a two-cluster solution was reproducible, separation was weak and added little clinical information beyond the continuous axes. Stanford ADRC analyses showed selected fluid biomarker associations, but imaging and PET results did not provide consistent support. In UK Biobank, projected axes were more strongly related to APOE genotype and systemic hematologic, renal, lipid, inflammatory, and hepatic traits than to clear dementia-risk replication. Plasma proteomics did not support robust Alzheimer's disease subtypes. Continuous molecular coordinates better describe plasma proteomic heterogeneity and may guide future biological stratification.