Plasma vitamin C levels are associated with brain structural networks on MRI: A large cohort study | PLOS One
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Abstract
Background
Neurodegenerative diseases significantly impact brain health in older adults, and although dietary vitamin C intake has been associated with a reduced risk of cognitive impairment, it remains unclear whether plasma vitamin C levels independently affect brain structure and neural connectivity. This study aimed to investigate whether plasma vitamin C levels were independently associated with brain volume and default mode network (DMN) connectivity in older adults.
Methods
All participants underwent 3T magnetic resonance imaging (MRI). Total intracranial volume (ICV), gray matter volume (GMV), and white matter volume (WMV) were calculated using CAT 12 in SPM 12. DMN connectivity was assessed using independent component analysis, based on shared GMV variance across voxels, and quantified by the loading coefficients. Multiple regression analysis was used to investigate the associations among brain volume, DMN connectivity measurements, and plasma vitamin C levels. These analyses were adjusted for potential confounders (age, sex, Mini-Mental State Examination score, diabetes, hypertension, hyperlipidemia, and education levels), and lifestyle factors (smoking history, drinking history, and physical activity). GMV/ICV ratio and WMV/ICV ratio were calculated to adjust for individual differences in head size.
Results
This cross-sectional study included 2,044 participants (median age, 69 years; females, 61.1%). Low plasma vitamin C levels were significantly and independently associated with the GMV/ICV ratio (p<br>Conclusions
In conclusion, our findings demonstrate that plasma vitamin C levels are positively associated with the structural integrity of the gray matter and DMN connectivity, generating the hypothesis that vitamin C may play a role in brain health.
Citation: Nagaya H, Watanabe K, Shintaku T, Sasaki M, Kudo J, Kasai S, et al. (2026) Plasma vitamin C levels are associated with brain structural networks on MRI: A large cohort study. PLoS One 21(6):<br>e0348504.
https://doi.org/10.1371/journal.pone.0348504<br>Editor: Branko Aleksic, Nagoya University: Nagoya Daigaku, JAPAN<br>Received: January 24, 2026; Accepted: April 16, 2026; Published: June 10, 2026<br>Copyright: © 2026 Nagaya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br>Data Availability: Data cannot be shared publicly because they contain sensitive participant information from the Iki-Iki Health Promotion Project. De-identified data are available from the Hirosaki University School of Medicine (contact via e-mail: coi@hirosaki-u.ac.jp) for researchers who meet the criteria for access to confidential data. Access requests must be approved by the research ethics review committees of the Hirosaki University School of Medicine and the researchers’ own affiliations.<br>Funding: The funder (KAGOME CO., LTD.) provided support in the form of salaries for authors D.K. and Y.U., but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. Additionally, this research was supported by the Japan Agency for Medical Research and Development (AMED) under Grant Numbers JP16dk0207025 and JP21dk0207053.<br>Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: A company (KAGOME CO., LTD.) established a department at Hirosaki University in Japan. The company is engaged in a health-promoting business. Two authors (Daichi Kokubu and Yusuke Ushida) are employees of the company. Two authors hold stock in the company. This study reflects the views of the scientists, not the company. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Introduction<br>Vitamin C is essential for improving brain health. It is a crucial antioxidant in the brain that plays a role in several biological functions, including acting as a cofactor in various enzymatic reactions, serving as a neuromodulator, and being involved in regulating certain peptide hormones. Human studies have reported that vitamin C concentrations are more than 2-fold higher in the cerebrospinal fluid (micromolar range) compared to plasma levels [1,2]. In experimental study, vitamin C concentrations in mice neurons reached 10,000 μM [3]. The role of vitamin C in promoting brain function has been...