Matrix metalloproteinase-9 is associated with CX3CL1 on tau and amyloid biomarker pathways in APOE4 carriers

APOE ε4 carriers exhibit heightened pro-inflammatory responses and microglial dysregulation compared to non-carriers. CX3CL1 is a biomarker involved in microglial signaling and Alzheimer's disease. It can be cleaved by proteases such as matrix metalloproteinases (MMPs), which are associated with memory and vasculature remodeling. We examined the role of MMP-9 in the pathway involving the association of CX3CL1 with cerebrospinal fluid (CSF) biomarkers for amyloid and tau in APOE ε4 carriers (APOE4+) compared to non-carriers (APOE4-). We further examined the association between APOE4 groups and inflammatory profiles. CSF samples were collected from 115 cognitively unimpaired VA-eligible Veterans enrolled in the Brain Amyloid and Vascular Effects of Eicosapentaenoic Acid (BRAVE) study (NCT02719327). We found that Aβ42 and Aβ42/Aβ40 were lower in APOE4+ carriers compared to non-carriers. Additionally, p-tau217 was higher among APOE4+ participants compared to APOE4- participants; however, p-tau217/tau was not different between carrier groups. In moderated mediation models, MMP-9 mediated the effect of CX3CL1 on Aβ42/Aβ40, p-tau217/tau and p-tau217/Aβ42 among APOE4+ carriers only. Lastly, we found a correlation between CX3CL1 and a composite pro-inflammatory z score, as well as lower ICAM-1 and VCAM-1 baseline levels in the APOE4+ group. However, CX3CL1 correlated with an anti-inflammatory z score in the APOE4- group, suggesting different inflammatory roles of CX3CL1 in APOE4+ carriers vs non-carriers. These findings suggest that the association of MMP-9 and CX3CL1 plays a unique role in tau and amyloid regulation among APOE4+ carriers, and that early dysregulation of immune systems may occur in cognitively unimpaired APOE4+ individuals.