ORIGINAL RESEARCH article
Front. Aging Neurosci.
Sec. Alzheimer's Disease and Related Dementias
Volume 17 - 2025 | doi: 10.3389/fnagi.2025.1547394
Plasma neurofilament light chain mediates the effect of subsyndromal symptomatic depression on cognitive decline in older adults
Provisionally accepted
- 1Yantai Yuhuangding Hospital, Yantai, China
- 2Jiaozhou Branch of Shanghai East Hospital, Tongji University, Jiaozhou, China
- 3Tongji Hospital Affiliated to Tongji University, Shanghai, Shanghai, China
- 4Department of Neurology, National Neuroscience Institute, Singapore, Singapore
- 5Duke-NUS Medical School, Singapore, Singapore
- 6Department of Neurology, Yantaishan Hospital, Yantai, Shandong Province, China
- 7Department of Neurology, Yantai Yuhuangding Hospital, Yantai, Shandong Province, China
- 8Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai, China
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Objective: Subsyndromal symptomatic depression (SSD) is associated with an increased risk of cognitive impairment in non-demented older adults. However, the mechanism underlying this relationship remains unclear. This study aimed to investigate whether plasma neurofilament light chain (NfL) mediates the relationship between SSD and cognitive decline.Materials and methods: Data of 707 non-demented older adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort were analyzed. Geriatric Depression Scale (GDS) scores were collected at baseline, while plasma NfL levels and cognitive assessments were obtained at baseline, 1-year, and 2-year follow-up visits. SSD was defined as a GDS score of 1–5. Mediation analyses were performed to examine whether the rate of change in plasma NfL levels mediated the relationship between SSD and cognitive decline.Results: Participants with SSD exhibited a greater increase in plasma NfL levels and more pronounced declines in global cognition, memory, executive function, language, and processing speed over 2 years compared to non-SSD participants. The rate of change in plasma NfL levels significantly mediated the relationship between SSD and accelerated cognitive decline, particularly in global cognition, memory, language, and processing speed.Conclusion: Plasma NfL, which is related to neuroaxonal damage, may partially mediate the association between SSD and accelerated cognitive decline in non-demented older adults. These findings suggest that dynamic changes in plasma NfL levels may reflect early neurobiological alterations associated with SSD and could help identify individuals at increased risk of cognitive deterioration over a 2-year period.
Keywords: Subsyndromal symptomatic depression, Cognition, neurofilament light chain, Mediation analysis, Alzheimer's disease
Received: 18 Dec 2024; Accepted: 28 Apr 2025.
Copyright: © 2025 Zhang, Li, Ng, Huang, Wang, Kong and Ba. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Maowen Ba, Department of Neurology, Yantai Yuhuangding Hospital, Yantai, Shandong Province, China
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