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Oxidative stress (OS) has been implicated in age-related neurodegeneration and may be important in prodromal states such as mild vascular cognitive impairment (mVCI). Higher peripheral OS is reported in mVCI patients; however, the role of central antioxidant defenses in mVCI is unclear. Glutathione (GSH) is a major brain antioxidant, and so brain GSH in possible mVCI vs. controls was assessed. Possible mVCI patients (1 standard deviation (SD) below population norms in verbal memory, executive function (EF), processing speed, or working memory, age 55-85, and currently enrolled in a cardiac rehabilitation program due to having 2 or more vascular risk factors or previous vascular event) and cognitively normal (CN) controls are recruited from a 6-month exercise rehabilitation program. All participants received 1H magnetic resonance spectroscopy (MEscher–GArwood Point Resolved Spectroscopy) to quantify brain GSH at baseline in the anterior cingulate (AC) and occipital cortex (OC). Spectroscopic analysis was completed using the Gannet toolkit (vers. 3.1) in Matlab (vers. 2020b). In 28 participants (mVCI n = 14, CN n = 14), after correcting for cerebrospinal fluid volume, anterior cingulate (AC) GSH (I.U. ± SD) was higher in mVCI (2.67 ± 0.29) compared to CN (2.25 ± 0.67) (F (1,25) = 4.7, P = 0.04) but not in the occipital cortex (OC, F (1, 25) = 1.3, p = 0.27). Higher AC-GSH was correlated with lower Montreal Cognitive Assessment score (rho (24) = -0.46 p = 0.02). In mVCI participants, higher AC-GSH also correlated with lower EF composite score (r (12) = -0.55 p = 0.04). Preliminary data suggest an upregulation in anterior cingulate glutathione in mVCI, which might reflect a compensatory increase in antioxidants as a response to increase peripheral oxidative stress previously reported in these patients. Recruitment is ongoing and additional participants are needed to reinforce findings. Canadian Institute of Health Research (#376204), the Alzheimer's Association Part the Cloud™ (PTC-18-543823), and the Alzheimer Society of Canada Research Program (21-11) [ABSTRACT FROM AUTHOR]