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

Abstract

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. The present study investigated the associations of cerebrospinal fluid (CSF) ferritin, an indicator for brain iron load, with neurodegenerative and inflammatory changes in AD. 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. 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. 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.