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.
Abstract
Alzheimer's disease (AD) unfolds over decades preceding cognitive symptoms, and measuring the full scope of its molecular complexity remains difficult. Blood-based biomarkers of amyloid, phosphorylated tau, astrocytic reactivity and neuroaxonal injury including A{beta}42/40, p-tau181, p-tau217, GFAP and NfL enable scalable assessment of AD-related pathology and associated processes but capture only a narrow slice of the systemic biology ultimately shaping disease progression. Here we link these increasingly routine clinical assays to the plasma proteome using multi-omic linear modeling to resolve functional heterogeneity in AD progression. In 484 older adults spanning normal cognition, mild cognitive impairment (MCI) and AD, we derived proteomic signatures for each key biomarker across more than 6,000 proteins, uncovering overlapping and distinct biological processes and cell types implicated in AD with robust signal across proteomic modalities. From these we built continuous progression-focused functional modules that were consistently preserved across 12 independent cohorts comprising 11,042 participants from the Global Neurodegeneration Proteomics Consortium and that associated with cognitive decline, diagnosis and AD-relevant biology. A synaptic vesicle module marked apparent neuronal resilience as much as 5 years before estimated symptom onset. We show 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.
A multivariate blood-based framework integrating 19 molecular assays and six risk instruments in the Bio-Hermes-001 cohort supports resilience and resistance as molecularly distinct subgroups and provides a scalable framework for pathology-informed stratification and mechanistic investigation.
K. Mavromati, C. Dalby, A. Dibble et al.· medRxiv· 0 citations
A stratified approach based on amyloid status is essential for the optimal application of blood-based biomarkers in monitoring disease progression and evaluating therapeutic efficacy in future clinical trials and precision medicine.
Keun You Kim, Hyunsun Ham, E. Yoon et al.· The journal of prevention of...· 0 citations
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
In this large longitudinal sample of asymptomatic individuals, the Aβ-dominant biomarker component showed the strongest association with longitudinal GM atrophy and cognitive decline, beyond the effects of tau pathophysiology and neuroaxonal injury.
W. Pelkmans, R. Cacciaglia, Michalis Kassinopoulos et al.· Molecular Neurodegeneration· 0 citations
Higher plasma YKL‐40 was associated with greater white matter hyperintensity (WMH), whereas higher plasma GFAP was related to increased 18F‐florbetapir (FBP) standardized uptake value ratio (SUVR) and higher plasma p‐tau217 was associated with reduced MTL cortical thickness and hippocampal volume.
Batool Rizvi, Jenna N. Adams, Alison R. Bamford et al.· Alzheimer's & Dementia· 1 citation
The introduction of blood-based biomarkers (BBMs) for Alzheimer’s disease (AD) represents one of the most transformative advances in neurodegenerative disease research over the past decade. 1,2 For the first time, biological evidence of AD pathology can be obtained through a minimally invasive, scalable blood test, opening new opportunities for early diagnosis, patient triage, and implementation of disease-modifying therapies. 3 Among the available biomarkers, phosphorylated tau (p-tau) species, particularly plasma p-tau217, have consistently shown excellent diagnostic performance across the AD continuum, recently culminating in regulatory approval of plasma p-tau217-based assays in both the USA and Europe. 4–6 Despite this remarkable clinical success, a fundamental paradox remains. Plasma tau biomarkers work
Lucilla Parnetti, L. Gaetani· EBioMedicine· 0 citations
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