Most plasma proteomic studies in Alzheimer's disease (AD) compare cases and controls cross-sectionally, leaving unresolved which AD-associated proteins mark diagnostic states and which are linked to disease progression. Using longitudinal SomaScan profiling from the Global Neurodegeneration Proteomics Consortium (13,449 participants, 17,269 samples, 7,362 aptamers), we separated baseline AD differences from AD-specific change over time. Linear mixed-effects models requiring concordant baseline and AD-by-time effects defined a 30-protein signature. We prioritized proteins across five evidence domains: clinical progression, AD biomarker alignment, cerebrospinal fluid concordance, independent prospective replication in UK Biobank and genetic support from Mendelian randomization and rare-variant burden. Thirteen proteins were supported in two or more domains and six in three. EDA2R, HPGDS, ITGAV and CLEC3B converged across clinical, biomarker and prospective evidence. Signature proteins aligned more strongly with tau and neuronal-injury markers than with Ab42/40. ANTXR1 showed direction-concordant plasma pQTL Mendelian randomization and nominal rare-variant burden signals, supporting its prioritization within the longitudinal AD signature. By distinguishing diagnostic-state markers from progression-linked changes, this longitudinal, multi-domain approach prioritizes proteins for validation as markers of AD progression and for mechanistic and therapeutic follow-up.
Junyoung Park, Y. le Guen, A. Peña-Tauber et al.· medRxiv· 0 citations
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.
Routine and accessible plasma measures can be leveraged to recover reproducible, biologically distinct progression modules that improve characterization of heterogeneous AD and have practical value for risk stratification, trial enrichment, or treatment monitoring.
R. R. Butler, M. P. Brown, A. Weber et al.· medRxiv· 0 citations