Abstract
Brain iron elevation is implicated in Alzheimer's disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer's risk allele, APOE-ɛ4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ɛ4 being the major genetic risk factor for AD.
Highlights
Brain iron elevation is implicated in Alzheimer’s disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study
We show that cerebrospinal fluid (CSF) ferritin levels have similar utility compared with more established AD CSF biomarkers, the tau/Ab1–42 ratio and apolipoprotein E (ApoE) levels, in predicting various outcomes of AD
Neither were there changes in ferritin levels when we separated the cohort according to CSF Ab1–42 levels (192 ng l À 1 cutoff; as proposed previously16) to reflect likely cerebral amyloid burden (ANCOVA: P 1⁄4 0.946; Supplementary Fig. 1)
Summary
Brain iron elevation is implicated in Alzheimer’s disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer’s risk allele, APOE-e4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-e4 being the major genetic risk factor for AD. We examined the association of baseline CSF-ferritin data with biomarker, cognitive, anatomical and diagnostic outcomes over 7 years in the Alzheimer’s disease Neuroimaging Initiative (ADNI) prospective clinical cohort. The nature of the relationship between CSF ferritin levels and cognitive performance was different from the other biomarkers, and, in contrast, CSF ferritin appears as a trait variable, and not a marker of disease
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