Systematic proteomics in Autosomal dominant Alzheimer’s disease reveals decades-early changes of CSF proteins in neuronal death, and immune pathways

Abstract

Background To date, there is no high throughput proteomic study in the context of Autosomal Dominant Alzheimers disease (ADAD). Here, we aimed to characterize early CSF proteome changes in ADAD and leverage them as potential biomarkers for disease monitoring and therapeutic strategies. Methods We utilized Somascan 7K assay to quantify protein levels in the CSF from 291 mutation carriers (MCs) and 185 non-carriers (NCs). We employed a multi-layer regression model to identify proteins with different pseudo-trajectories between MCs and NCs. We replicated the results using publicly available ADAD datasets as well as proteomic data from sporadic Alzheimers disease (sAD). To biologically contextualize the results, we performed network and pathway enrichment analyses. Machine learning was applied to create and validate predictive models. Findings We identified 125 proteins with significantly different pseudo-trajectories between MCs and NCs. Twelve proteins showed changes even before the traditional AD biomarkers (Aβ42, tau, ptau). These 125 proteins belong to three different modules that are associated with age at onset: 1) early stage module associated with stress response, glutamate metabolism, and mitochondria damage; 2) the middle stage module, enriched in neuronal death and apoptosis; and 3) the presymptomatic stage module was characterized by changes in microglia, and cell-to-cell communication processes, indicating an attempt of rebuilding and establishing new connections to maintain functionality. Machine learning identified a subset of nine proteins that can differentiate MCs from NCs better than traditional AD biomarkers (AUC>0.89). Interpretation Our findings comprehensively described early proteomic changes associated with ADAD and captured specific biological processes that happen in the early phases of the disease, fifteen to five years before clinical onset. We identified a small subset of proteins with the potentials to become therapy-monitoring biomarkers of ADAD MCs.

Synapse protein signatures in cerebrospinal fluid and plasma predict cognitive maintenance versus decline in Alzheimer’s disease

“…We included PC1 of the proteome as a covariate, because previous studies have shown that it represents a large source of non-disease related variance, potentially related to heterogeneity in CSF production/clearance rates 65,67 . Inclusion of PC1 "denoised" the data greatly improved the significance of protein associations with cognitive impairment in every cohort we assessed.…”

Ubiquitin-Proteasome System in the Different Stages of Dominantly Inherited Alzheimer’s Disease

“…Leveraging the high-throughput capabilities of the SOMAscan proteomics platform and data from the Dominantly Inherited Alzheimer Network (DIAN), we explored the changes in expression, stability, and modi cations of UPS proteins throughout the disease course. Considering existing evidence that abnormal accumulation of Aβ and tau proteins in the brain in AD begins well before the onset of neurological symptoms, up to 20 years prior, we investigated the early accumulation of both Aβ and tau aggregated protein species in relation to UPS dysregulation in DIAD 28,30,31,32,33 . We aimed to explore if dysregulation of UPS proteins impacts the progression of DIAD by assessing the associations with Aβ, and tau pathologies, neuronal loss, and neuroin ammation (all measured using existing established CSF and neuroimaging biomarkers) and clinical symptoms.…”