Plasma protein profiling reveals novel specific biomarkers reflecting the multifactorial nature of Alzheimer´s disease continuum

Abstract

AbstractBackgroundPlasma‐based biomarkers able to depict the molecular diversity associated to Alzheimer´s disease (AD) are needed to better track disease progression and for developing biological therapies targeting different pathomechanisms. Here we aimed to identify plasma protein changes covering different biological pathways along the AD continuum and specific for this neurodegenerative disease.MethodProximity extension‐based multiplex immunoassays were used to analyse 1572 proteins in 1003 plasma samples collected from 6 international centres (JPND bPRIDE consortium), including 330 cognitively unimpaired (CU) controls (CTRL) with negative amyloidosis biomarkers, 164 CU subjects with positive amyloidosis biomarkers (preAD), 129 MCI due to AD (MCI‐AD), 137 AD at dementia stage (AD‐dem), 171 Dementia with Lewy Bodies (DLB) and 170 Frontotemporal dementia (FTD) patients (see Table 1). Data were analysed using nested linear models adjusted for multiple testing and penalized regressions.ResultWe detected >200 proteins differentially regulated along the AD continuum compared to CTRL (q<0.05). More than 300 of the proteins differentially regulated at AD‐dem were also changed between AD‐dem and FTD/DLB (e.g., CALCOCO1, MAP3K5, BIN2, GFAP). Enrichment in pathways related to autophagy, ubiquitination, mitotic cell cycle and protein kinase activity was detected along the AD continuum. GFAP showed the strongest performance to discriminate any AD stage from CTRL (AUCs 0.68‐0.82) as well as AD from FTD (0.75 AUC). SUSD1 showed the strongest performance to discriminate AD from DLB (AUC 0.77). Most promising biomarker candidates are shown in Figure 1. We identified panels (17‐21 proteins) discriminating MCI‐AD or AD‐dem from controls and AD‐dem from FTD or DLB with AUCs>0.80. Proteins within these panels are associated to different biological functions (e.g., phagocytosis, myelination, endolysosomal system, calcium signalling, energy metabolism). All the proteins that discriminated both MCI‐AD and AD‐dem from CTRL (Figure 1, e.g., GFAP, MAP3K5, CALCOCO1, TNFSF10) showed an incremental increase/decrease from preclinical to dementia AD stages.ConclusionThis unprecedent large proteome study unveils novel plasma protein changes along the full AD continuum associated to processes involved in AD pathophysiology. We identified plasma protein panels depicting the biological diversity of this neurodegenerative disease. Customized multiplex assays will be developed for these panels for widespread validation in clinical settings and trials.