Proteins Associated with Cognition in Amyloid-beta Positive Elders Based on Cerebrospinal Fluid Proteomics

In the pathogenesis of Alzheimer's disease (AD), amyloid-beta (Aβ) is widely recognized as a core pathological hallmark and an upstream factor contributing to cognitive decline. However, not all individuals with Aβ pathology inevitably develop cognitive impairment or progress to AD. To date, the key proteins associated with cognitive progression in Aβ-positive (A +) individuals have not been fully identified. This study aimed to identify such proteins in A + participants, defined by cerebrospinal fluid (CSF) Aβ₄₂ levels and Aβ positron emission tomography (PET) imaging, using CSF proteomics. We analyzed 6,361 CSF proteins from 490 A + participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Baseline differences in protein expression were examined between the A + with AD dementia group and the A + non-demented group, which included cognitively normal (CN) and mild cognitive impairment (MCI) participants. Associations between dysregulated proteins and both cognitive progression and diagnostic conversion were investigated using linear mixed-effect (LME) and Cox proportional-hazard models, with a mean follow-up of 3.65 years. Functional enrichment was assessed through Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. We identified 61 dysregulated proteins, including 47 upregulated and 14 downregulated, in the A + with AD dementia group compared with the A + non-demented group. Of these, 39 key proteins (significantly associated with all five cognitive scales and diagnostic conversion) and 14 candidate proteins (associated with at least one cognitive measure) were linked to cognitive progression. Notably, 14-3-3 proteins (YWHAG, YWHAZ, YWHAB) were strongly associated with cognitive decline, particularly in the early stage of AD, and YWHAG, MMP10, and NEFH were associated with a higher risk of cognitive diagnostic conversion than classical CSF AD biomarkers. GO enrichment analysis revealed that these dysregulated proteins were significantly enriched in pathways related to cognition, learning, or memory. These findings may provide potential targets for early diagnosis and therapeutic intervention in AD.