Systemic Proteomic and Organ Aging Signatures Associated with plasma Aβ Oligomerization in a Korean cohort: A Cross-Sectional Study

Abstract

Background: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta (Aβ) in the brain, which begins decades before the appearance of clinical symptoms. Blood from AD patients, when spiked with synthetic Aβ, exhibited a higher Aβ oligomerization tendency (OAβT) than the non-AD subjects. OAβT reflected early pathological changes of AD, considered as a promising blood-based biomarker. However, the mechanism underlying OAβT remained elusive. This study aimed to identify proteomic signatures associated with OAβT and explore its role in AD diagnosis. Methods: Forty AD and non-AD subjects from a Korean cohort were divided into four groups based on the disease diagnosis, OAβT values (thresholded at 0.78 ng/mL), and amyloid PET status (A-PET): A-PET-positive AD patients with high or low OAβT values, A-PET-negative non-AD subjects with high or low OAβT values. Using aptamer-based proteomics, 7,288 proteins from plasma samples were quantified, and the group differences were assessed in protein levels and the enrichment of gene sets associated with annotations from the Gene Ontology database. Further, we assessed whether OAβT-PET mismatched cases (A-PET-positive but OAβT-low or A-PET-negative but OAβT-high) exhibited distinct blood proteome signatures in comparison to typical AD cases. Aging signatures for 11 organs were analyzed to explore systemic factors linked to OAβT-PET discrepancies. Additionally, the pharmacological influences on the OAβT-related proteome were investigated by comparing OAβT-correlated proteins with a database of drug-induced proteomic changes. Results: Elevated OAβT values, regardless of AD diagnosis, correlated with increased immune response and decreased cellular metabolism. Dementia-predicting proteins were enriched in non-AD individuals with high OAβT. Accelerated muscle aging was associated with high OAβT values and worse cognitive function. Furthermore, several potential pharmacological modulators of OAβT, including Minocycline and Anamorelin, were identified. Conclusion: Our findings demonstrated OAβT as a reflection of systemic changes linked to early AD pathology. Moreover, the influence of medications and systemic aging on OAβT values pointed the potential avenues for intervention and emphasized the importance of considering systemic factors in AD pathogenesis and treatment.