The Associations of Cerebrospinal Fluid Ferritin with Neurodegeneration and Neuroinflammation Along the Alzheimer’s Disease Continuum

Article type: Research Article

Authors: Pan, Rui^{a; 1} | Luo, Shuyi^{b; 1} | Huang, Qing^c | Li, Weiwei^d | Cai, Tianshu^e | Lai, Kelin^d | Shi, Xiaolei^{f; g; *} | for the Alzheimer’s Disease Neuroimaging Initiative²

Affiliations: [a] School of Nursing, Huizhou Health Sciences Polytechnic, Huizhou, Guangdong Province, P. R. China | [b] Department of Cardiothoracic Surgery, The Third People’s Hospital of Huizhou, Huizhou, Guangdong Province, P. R. China | [c] School of Foreign Languages, Huizhou University, Huizhou, Guangdong Province, P. R. China | [d] School of Clinical Medicine, Huizhou Health Sciences Polytechnic, Huizhou, Guangdong Province, P. R. China | [e] School of Medicine and Medical Laboratory Science, Huizhou Health Sciences Polytechnic, Huizhou, Guangdong Province, P. R. China | [f] Geriatric Neuroscience Center, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, P. R. China | [g] Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou, Guangdong Province, P. R. China

Correspondence: [*] Correspondence to: Xiaolei Shi, MD, PhD, Center for Geriatric Neuroscience, The Affiliated Brain Hospital of Guangzhou Medical University; Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou, China. E-mail: shixl@gzhmu.edu.cn.

Note: [1] These authors contributed equally to this study.

Note: [2] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Abstract: Background:Increasing evidence has suggested that iron accumulation plays an important role in the onset and development of Alzheimer’s disease (AD). However, the potential mechanism remains unclear. Objective:The present study investigated the associations of cerebrospinal fluid (CSF) ferritin, an indicator for brain iron load, with neurodegenerative and inflammatory changes in AD. Methods:The study involved 302 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). They were classified as normal controls (A–T–N–, n = 48), AD continuum (A+TN–, n = 46; A+TN+, n = 166), and suspected non-AD pathology (A–TN+, n = 42), according to the amyloid/tau/neurodegeneration (ATN) system. Group comparisons of CSF ferritin among groups were performed using one-way ANOVA. Linear regression models were used to test the relationships between CSF ferritin and cognitive assessments, and the associations between CSF ferritin and other biomarkers, respectively. Results:We found that CSF ferritin showed significant differences among the ATN groups, with higher concentration in more advanced categories (A+TN+). Furthermore, CSF ferritin level was independently related to cognitive performance (MMSE, ADAS-Cog13, and ADNI-mem). Linear regression analysis indicated positive relationships between CSF ferritin and phosphorylated tau and total tau, rather than Aβ42. Significant associations were revealed between CSF ferritin and inflammatory proteins, including TNF-α, TNFR1, TNFR2, ICAM1, VCAM1, TGF-β1, IL-9, and IP-10, respectively. Conclusion:Our results provide new insight into iron dysfunction in AD pathology and highlight elevated brain iron as a possible mechanism of neurodegeneration and neuroinflammation along AD continuum.

Keywords: Alzheimer’s disease, cerebrospinal fluid, ferritin, neurodegeneration, neuroinflammation

DOI: 10.3233/JAD-220002

Journal: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 1115-1125, 2022