Complement C4b and factor B in astrocyte-derived exosomes as novel biomarkers for amnestic mild cognitive impairment

Neuroinflammation represents a fundamental pathological mechanism underlying amnestic mild cognitive impairment (aMCI), with dysregulated activation of the complement system playing a pivotal role. Astrocyte-derived exosomes (ADEs), which are capable of traversing the blood-brain barrier (BBB), offer a non-invasive means to investigate central nervous system pathology. This study explored the diagnostic potential of two principal complement components, C4b and factor B (FB), within plasma-derived ADEs for aMCI and analyzed their interaction with the ApoE ε4 allele. We enrolled 99 aMCI patients and 96 demographically matched normal controls (NC). C4b and FB levels in plasma-derived ADEs were quantified using ELISA, and all participants underwent ApoE genotyping. In the total cohort, levels of both C4b and FB in ADEs were significantly elevated in the aMCI group compared to NC. Diagnostic model validation demonstrated that adding C4b alone or in combination with FB to a baseline model significantly improved diagnostic performance, whereas adding FB alone provided no significant benefit. Notably, the ApoE ε4 genotype exerted a precise modulatory effect: among ApoE ε4 non-carriers, C4b levels were elevated in the aMCI group but did not yield significant diagnostic improvement; in contrast, among ApoE ε4 carriers, both C4b and FB were specifically upregulated, and only their combination achieved excellent diagnostic performance (AUC = 0.833; DeLong's test, P = 0.017), whereas neither marker alone was effective. Furthermore, C4b exhibited broader and more significant correlations with cognitive function compared to FB. This study substantiates that ADE-derived C4b serves as a reliable diagnostic biomarker for aMCI, whereas the diagnostic efficacy of FB is contingent upon ApoE ε4 allele status. Consequently, we propose a precision diagnostic strategy that involves the concurrent assessment of C4b and FB specifically in individuals carrying the ApoE ε4 allele, thereby presenting a novel approach for the early detection of aMCI.