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

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.