Copper/zinc superoxide dismutase (SOD1) scavenges free radicals that may otherwise damage brain parenchyma. Impaired SOD1 activity drives AD neuropathology in animal models and post-mortem AD brains. Yet, it is unknown how CSF SOD1 is related in vivo to AD-relevant cognitive, neuroimaging, and CSF neurotoxic factors, and what potential mechanisms underlie these associations.
We found that higher CSF SOD1 correlated with better global cognition scores, yet less gray matter (GM) and glucose metabolism in AD-sensitive parietal and frontal regions. Higher CSF SOD1 was also associated with more CSF total tau and phosphorylated tau-181, but not beta-amyloid (Aβ) 1-42. Through mediation analyses, higher total tau largely mitigated higher CSF SOD1 and better global cognition associations, and it fully accounted for less predicted regional GM but not glucose metabolism. Among participants who developed AD over 2 years or had AD at baseline, higher CSF SOD1 was initially related to more regional GM. This association became non-significant with full mediation via higher CSF total tau, whereby higher CSF SOD1 predicted more total tau and in turn less GM.
Our observations lead to the hypothesis that SOD1 antioxidation reflects tau but not amyloid accumulation, which may lead to prooxidant-based neurodegeneration and cognitive dysfunction.
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