Levels of ferritin in cerebrospinal fluid (CSF) are independently related to cognitive performance and predict progression from mild cognitive impairment (MCI) to Alzheimer’s disease, according to a new study by Australia-based Alzheimer’s Disease Neuroimaging Initiative (ADNI) researchers published in Nature Communications. Ferritin levels also were strongly associated with apolipoprotein E (APOE) levels and were elevated by the Alzheimer’s risk allele, APOE-ε4. The findings introduce brain iron elevation as a possible mechanism for APOE-ε4 being the major genetic risk factor for Alzheimer’s disease, according to the researchers.

Brain iron elevation has been observed in Alzheimer’s disease, but CSF ferritin levels in this population have not been studied extensively. ADNI researchers compared baseline CSF ferritin levels with biomarker, cognitive, anatomical, and diagnostic outcomes over 7 years in the ADNI prospective clinical cohort. They did not find substantively different CSF ferritin levels among cognitively normal, MCI, and Alzheimer’s disease subjects. However, they found an inverse relationship between subjects’ cognitive scores and their ferritin levels. Among subjects with Alzheimer’s disease, those in the highest tertile of ferritin levels had scores about three points worse on the Alzheimer’s Disease Assessment Scale compared with Alzheimer’s patients with CSF ferritin levels in the lowest tertile. The magnitude of this cognitive difference was similar to that observed in patients with high CSF tau-beta-amyloid ratio.

Cognitively normal subjects and those with MCI who had the highest ferritin levels also scored lower on a verbal learning test than did those with lower ferritin levels. The researchers did not find higher CSF ferritin levels to be linked to a higher rate of cognitive decline over time, but rather found CSF ferritin associated with a static level of cognitive loss at all stages of disease.

Patients with MCI who had high ferritin levels met the criteria for Alzheimer’s disease earlier than those with lower levels, about 9 months earlier for every standard deviation increase.