Iron species in cerebrospinal fluid and dementia risk in subjects with mild cognitive impairment: A cohort study

Background: Iron dysregulation has been implicated in the pathogenesis of dementia, since it is an essential nutrient for neuronal function, but also contributes to oxidative stress and neurotoxicity at elevated levels. Methods: We enrolled 56 individuals with newly-diagnosed mild cognitive impairment (MCI) and followed over a 47-month period to monitor conversion to dementia according to baseline percentage concentrations of cerebrospinal fluid iron species. Results: In this cohort, 28 participants developed Alzheimer's dementia, 5 frontotemporal dementia, 2 Lewy body dementia, and 2 vascular dementia during the follow-up. Higher Fe-Ferritin was associated with a higher though statistically unstable dementia risk (hazard ratio-HR 1.36 for 10-unit % increase, 95 % confidence interval-CI 0.88–2.11), while Fe-Transferrin was linked to a lower risk (HR 0.65, 95 % CI 0.21–2.08) and inorganic Fe showed little association (HR 1.06, 95 % CI 0.80–1.40). Patterns of association were non-linear: inorganic Fe had a U-shaped association, with reduced risk at 25–40 % and increased risk above 45 %; Fe-Ferritin showed an inverted U-shaped relation with higher risk between 10 % and 20 %; Fe-Transferrin showed almost no relation with dementia risk. When considering conversion to Alzheimer's dementia only, the relation was similarly U-shaped for inorganic Fe and almost null for Fe-Transferrin, while Fe-Ferritin showed a positive relation with risk above 15 %. Conclusions: Despite the statistical imprecision of the estimates, our study provides novel evidence linking iron species in cerebrospinal fluid to dementia risk in individuals with MCI. These findings also underscore the importance of elemental speciation in dementia research.