Systemic proteomic and organ aging signatures associated with plasma Aβ oligomerization in a Korean cohort: a cross-sectional study

초록

Background Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta (A beta) in the brain, which begins decades before the appearance of clinical symptoms. Blood from AD patients, when spiked with synthetic A beta, exhibited a higher A beta oligomerization tendency (OA beta T) than the non-AD subjects. OA beta T reflected early pathological changes of AD and is considered as a promising blood-based biomarker. However, the mechanism underlying OA beta T remained elusive. This study aimed to identify proteomic signatures associated with OA beta T 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, OA beta T values (thresholded at 0.78 ng/mL), and amyloid PET status (A-PET): A-PET-positive AD patients with high or low OA beta T values, A-PET-negative non-AD subjects with high or low OA beta T 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 OA beta T-PET mismatched cases (A-PET-positive but OA beta T-low or A-PET-negative but OA beta T-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 OA beta T-PET discrepancies. Additionally, the pharmacological influences on the OA beta T-related proteome were investigated by comparing OA beta T-correlated proteins with a database of drug-induced proteomic changes.Results Elevated OA beta T 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 OA beta T. Accelerated muscle aging was associated with high OA beta T values and worse cognitive function. Furthermore, several potential pharmacological modulators of OA beta T, including Minocycline and Anamorelin, were identified.Conclusion Our findings demonstrated OA beta T as a reflection of systemic changes linked to early AD pathology. Moreover, the influence of medications and systemic aging on OA beta T values pointed to the potential avenues for intervention and emphasized the importance of considering systemic factors in AD pathogenesis and treatment.

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