Plasma Proteomic Profiling Reveals Divergent Molecular Pathways in Aging and Alzheimer’s Disease

Background Dementia is a progressive disorder characterized by memory impairment and cognitive decline; however, the systemic molecular alterations associated with aging and dementia remain incompletely understood. In this study, we performed mass spectrometry-based plasma proteomic profiling in two independent cohorts to identify molecular signatures linked to cognitive function. Methods In the healthy aging cohort, 2,411 proteins were identified from 119 successfully analyzed plasma samples collected from individuals aged 20–79 years. In the cognitive decline cohort comprising non-demented controls (NC; n = 20), patients with mild cognitive impairment (MCI; n = 20), and those with Alzheimer’s disease (AD; n = 20) diagnosed according to National Institute on Aging–Alzheimer’s Association criteria, 1,494 proteins were identified. Differential protein expression was assessed using permutation-based false discovery rate correction (FDR < 0.05). Results In the healthy aging cohort, plasma proteomic changes occurred gradually with age and were enriched in immune and inflammatory pathways. In contrast, the cognitive decline cohort showed distinct alterations enriched in actin- and platelet-related proteins. Cluster analysis revealed stage-specific molecular signatures emerging during the transition from normal cognition to mild cognitive impairment and AD. Integrated comparison of the two cohorts suggested that aging- and AD-associated proteomic changes followed divergent trajectories. Notably, among the proteins significantly altered in AD (FDR < 0.05), 80 have not previously been reported in plasma dementia studies. Conclusions Plasma alterations associated with cognitive decline are not merely an extension of normal aging but may reflect distinct systemic processes involving immune regulation, actin, and platelet function. These findings from a discovery cohort provide insight into systemic molecular mechanisms underlying cognitive decline and identify candidate blood-based biomarkers and potential therapeutic targets for dementia. Further validation in larger longitudinal studies with balanced cohort designs, appropriate statistical adjustments, and standardized experimental procedures are warranted.