Deciphering the components of Amyloid‐beta (Aβ)‐driven dementia using a novel peptide‐focused global proteomics platform

Abstract Background The overlap of Alzheimer’s disease (AD) symptomology and pathology with other dementia types is a significant challenge to treatment, patient care, and new drug development. Amyloid‐beta (Aβ) peptides begin to accumulate in AD subjects over a decade prior to clinical symptoms and impair multiple cellular pathways during disease continuum. However, how the brain proteome is remodeled by Aβ burden remains an enigma. Here we compared the cerebrospinal fluid (CSF) proteomes of demented subjects with or without Aβ pathology to unveil alterations specific to Aβ‐driven dementia. Method Mass spectrometry data (PRIDE archive PXD016278) from CSF of cognitively impaired Sweden cohort subjects was reanalyzed using our de novo ‐assisted workflow. Peptide raw peak area intensities were quantile normalized and log2 transformed to reduce technical variation and ensure distribution symmetry. Differentially expressed peptides were identified via analysis of covariance after adjusting for age and gender. Multiscale Embedded Gene Co‐expression Network Analysis (MEGENA) was used to explore the dysregulated network from Aβ ‐ driven brain proteome remodeling. Result The de novo ‐assisted workflow significantly increased the CSF proteome depth ‐ 4,572 CSF protein groups vs 1542 protein groups reported in PXD016278 analysis. Comparison of peptide‐level CSF proteomes of demented subjects with or without Aβ pathology identified 2,014 differentially regulated peptides (q<0.2). These alterations may reflect the Aβ ‐ driven brain proteome remodeling in CSF. MEGENA network analysis identified several hubs and network modules. The most significantly altered ALDO‐A peptide represented a hub, a highly connected node within a network module, and exhibited high correlation with AD‐linked neurosecretory protein VGF and MAPT. The top pathways enriched in MEGENA network modules, e.g. extracellular matrix organization, cell adhesion, and neurogenesis, are consistent with other pathway enrichment analyses across other cross‐sectional studies in AD and non‐AD dementias. Conclusion This is the first study capturing the peptide‐level alterations in CSF to reflect brain proteome remodeling by Aβ burden. This data will serve as an important resource for biomarkers demarcating AD from non‐AD.