Systemic oxidative stress in patients with Alzheimer's disease

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BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder and oxidative stress (OS) is believed to play a role in disease pathogenesis. However, reliable OS markers are lacking. In this study we aim to assess OS in AD by evaluating free thiols, which serve as key indicators of the systemic redox status. METHODS: SCD (subjective cognitive decline), MCI (mild cognitive impairment), AD, and other dementias (Non-AD) were recruited. Comorbidity data were collected and free thiols were measured in plasma. Additionally, phosphorylated-Tau (pTau217), amyloid-beta ratio (Aβ42/40), Glial Fibrillary Acidic Protein (GFAP), and neurofilament light (NfL) levels were used to investigate correlation with free thiols. Further, associations between free thiols and disease severity in AD were calculated. RESULTS: Three hundred and ten patients were included (SCD 109, MCI 51, AD 125, Non-AD 25). Free thiols were significantly lower in AD compared to SCD and MCI (p<0.01). Free thiols correlated negatively with pTau217, NfL and GFAP, also within AD (p<0.01 for all). Additionally, free thiols significantly negatively correlated with Montreal Cognitive Assessment (MOCA) scores (N=210, p<0.001). Multiple linear regression showed that type 2 diabetes and age were significant predictors for free thiols (B=1.01, β=0.266, p<0.001; B=-0.040, β=-0.273, p<0.001, respectively). After adjusting for these covariates, free thiols remained significantly lower in AD compared to SCD (p<0.05). CONCLUSION: Increased systemic OS, reflected by lower free thiols, is observed in plasma of AD patients, supporting a key role for OS in AD-pathophysiology and highlighting free thiols as potential therapeutic targets and possibly complementary biomarkers for clinical diagnostics.