Introduction

Hippocampal atrophy is recognised as a specific marker for tracking disease progression in Alzheimer’s disease (AD)¹. Cerebrospinal fluid (CSF) ferritin² and ceruloplasmin³, cellular proteins that store iron and export iron, respectively, are associated with AD pathology, suggesting iron dysregulation operates in AD. The aim of this study was to determine the relationship between iron regulatory proteins, Aβ and tau (AD biomarkers), neuroinflammation indicated by glial fibrillary acidic protein (GFAP), an astrocyte marker, and osteopontin (expressed by reactive astrocytes and microglia)⁴, with hippocampal volumes.

Methods

The following ADNI data was downloaded from age-matched 84 healthy control (HC), 124 mild cognitive impairment (MCI) and 55 AD subjects: CSF ceruloplasmin, ferritin, GFAP, osteopontin, Aβ, total tau and phosphorylated tau, MRI-derived volumes of hippocampus, entorhinal cortex, fusiform and ventricles acquired at 1.5T-MRI. Pearson’s correlation analysis was used to elucidate the relationship between CSF ceruloplasmin or ferritin with the other CSF measures and hippocampal volumes. If significant correlation was observed (p < 0.05) between ceruloplasmin or ferritin with hippocampal volume, a two-stage hierarchical multiple regression model was applied with ceruloplasmin at stage one of regression followed by GFAP, osteopontin, Aβ, total tau and phosphorylated tau at stage two, and hippocampal volume as the dependent variable.

Results and Discussion

CSF ceruloplasmin was not correlated with neuroinflammation, AD biomarkers or hippocampal volume in HC. Ceruloplasmin positively correlated with ferritin (R² = 0.036, p = 0.031), GFAP (R² = 0.052, p = 0.009) and osteopontin (R² = 0.048, p =0.012) in MCI and also in AD (figure 1). However, in the latter, ceruloplasmin also negatively correlated with hippocampal atrophy (R² = 0.132, p = 0.002). Hierarchical multiple regression testing demonstrated that ceruloplasmin significantly contributed to the regression model accounting for 12.3% of the variation in hippocampal volume, with GFAP (β = -0.535, p = 0.005) and total tau (β = 0.471, p = 0.019) explaining an additional 22.4% of the variation. Ferritin positively correlated with GFAP (R² = 0.141, p < 0.001) and osteopontin (R² = 0.116, p <0.001) in HC but also correlated to ceruloplasmin, total tau (R² = 0.093, p < 0.001) and phosphorylated tau (R² = 0.068, p = 0.003) in MCI whereas ferritin positively correlated to ceruloplasmin (R² = 0.152, p = 0.002), GFAP (R² = 0.279, p < 0.001) and osteopontin (R² = 0.194, p = 0.001) in AD. Increased CSF ferritin seems to be associated with inflammation in the elderly and may interact with tau metabolism to drive early AD pathology⁴. CSF ceruloplasmin, on the other hand, appears to act in synergy with astrogliosis and tau metabolism in AD to increase hippocampal atrophy and enhance AD pathology.

Conclusion

Ceruloplasmin and ferritin are involved in iron metabolism which appears dysregulated in AD⁵ and supports therapies to restore metal homeostasis may be beneficial to AD.

Acknowledgements

No acknowledgement found.

References

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