Study Finds SOD1 Antioxidant Loses Protective Effect as Tau Builds in Alzheimer’s Disease

Summary: Early in Alzheimer’s disease, the antioxidant enzyme SOD1 helps reduce levels of tau protein and supports cognitive function. As tau accumulates, however, SOD1’s protective role weakens, and its ability to prevent neurodegeneration diminishes.

Source: Iowa State University

New research from Iowa State University provides insight into a puzzling observation: the antioxidant superoxide dismutase 1 (SOD1), which defends the brain against oxidative damage, appears linked both to cognitive protection and to regions that later deteriorate in Alzheimer’s disease. The study suggests that SOD1 initially counters the toxic effects of tau proteins, but that its effectiveness declines as tau levels rise.

SOD1 neutralizes free radicals that can damage brain tissue, and in this study higher cerebrospinal fluid (CSF) SOD1 concentrations were associated with better global cognitive performance. Yet those same higher SOD1 levels also correlated with reduced gray matter and lower glucose metabolism in brain regions vulnerable to Alzheimer’s pathology. Crucially, increased CSF total tau and phosphorylated tau-181 largely explained these contradictory associations, while levels of beta-amyloid (Aβ1-42) did not.

“In individuals with Alzheimer’s or mild cognitive impairment, SOD1 was related to more gray matter, which is significant for memory,” said Kelsey McLimans, a recent Ph.D. graduate and research assistant in food science and human nutrition. “However, our results show 90 percent of this positive association is negated by tau. This bolsters our hypothesis that SOD1 itself isn’t detrimental; it’s just trying to limit the oxidative damage caused by tau.”

The research team—led by Kelsey McLimans and Bridget Clark and supervised by Auriel Willette—analyzed data from 287 adults aged 65 to 90 enrolled in the Alzheimer’s Disease Neuroimaging Initiative. Participants included individuals with no cognitive impairment, those with mild cognitive impairment, and people diagnosed with Alzheimer’s disease. This study is the first to identify in living humans a link between CSF SOD1 and tau biomarkers across stages of cognitive decline.

How tau undermines antioxidant defenses

The investigators propose that SOD1 activity initially reflects the brain’s attempt to neutralize oxidative stress linked to tau accumulation. However, as tau pathology spreads, SOD1’s antioxidant effect becomes insufficient. Auriel Willette, assistant professor of food science and human nutrition, used the analogy of a spreading fire: when tau pathology expands beyond control, antioxidant defenses—even if elevated—cannot fully stop the resulting neurodegeneration.

Using mediation analysis, the team found that higher total tau largely removed the beneficial association between elevated CSF SOD1 and global cognition, and fully explained the relationship between higher SOD1 and lower regional gray matter. In participants who either already had Alzheimer’s or developed it within two years, higher CSF SOD1 initially corresponded to greater regional gray matter. That association vanished after accounting for higher CSF total tau, suggesting that increased SOD1 may be a response to tau-driven damage rather than an independent protective factor long-term.

Implications for biomarkers and interventions

These findings support the hypothesis that SOD1 levels in CSF reflect tau pathology rather than amyloid-driven neurodegeneration. If confirmed in further research, CSF SOD1 could serve as a biomarker linked to tau-related oxidative stress and regional brain decline. The study also raises the possibility that strategies to sustain or enhance antioxidant defenses—through nutrition, lifestyle, or pharmacological means—might delay or modulate progression of tau-associated neurodegeneration, though the authors stress more studies are needed before practical recommendations can be made.

The research team includes Auriel Willette (principal investigator), Anumantha Kanthasamy (Distinguished Professor and chair of biomedical sciences), Vellareddy Anantharam, Alexandra Plagman, Colleen Pappas, and others. Their work appears in the journal Antioxidants & Redox Signaling and examines whether CSF SOD1 functions as a biomarker of tau but not amyloid-related neurodegeneration in Alzheimer’s disease.

Source:
Iowa State University

Media contacts:
Auriel Willette – Iowa State University

Image:
The image used in the study summary is in the public domain.

Original research:
“Is CSF SOD1 a Biomarker of Tau but not Amyloid Induced Neurodegeneration in Alzheimer’s Disease?” by Kelsey E. McLimans, Bridget E. Clark, Alexandra Plagman, Colleen Pappas, Brandon Klinedinst, Vellareddy Anantharam, Anumantha Kanthasamy, and Auriel A. Willette, published in Antioxidants & Redox Signaling.