Iron may underlie effect of Alzheimer’s risk allele

By Eleanor McDermid, Senior medwireNews Reporter

Ferritin in the cerebrospinal fluid (CSF) of patients with Alzheimer’s disease (AD) is associated with the APOE ε4 risk allele and predicts cognitive outcomes, a study shows.

“Collectively these data support consideration of therapeutic strategies that lower brain iron, which have reported beneficial outcomes in Phase II trials of Alzheimer’s and Parkinson’s diseases”, write the study authors in Nature Communications.

“Lowering CSF ferritin, as might be expected from a drug like deferiprone, could conceivably delay MCI [mild cognitive impairment] conversion to AD by as much as 3 years.”

Ashley Bush (The University of Melbourne, Victoria, Australia) and colleagues measured baseline CSF levels of ferritin, as an indicator of brain iron levels, in 302 participants of the US-based Alzheimer’s Disease Neuroimaging Initiative.

Cortical iron levels are reportedly elevated in AD, which, it is thought, may contribute to cognitive decline. In the current study, the team found that ferritin levels were related to participants’ baseline cognitive scores on the Alzheimer's Disease Assessment Scale, with levels in the top tertile (>7.2 ng/mL) associated with about a 3-point lower score compared with levels in the bottom tertile (<5.4 ng/mL).

Ferritin also predicted changes over time, but its effect on cognitive function was the same at all time points, identifying it as a trait variable, in contrast to the effects of disease markers such as APOE ε4, which increased over time.

Because of this constant effect, people with MCI who had high ferritin levels met the criteria for AD earlier than those with lower levels, with each standard deviation increase resulting in a 9.5-month shift to an earlier age of conversion. This compared with 18.2- and 8.6-month shifts for a standard deviation increase in ApoE and the ratio of tau to β-amyloid (Aβ)_1–42, respectively.

Adding ferritin to a model containing these two markers plus age, gender, education and body mass index increased the model’s predictive accuracy for conversion to AD “markedly”, from 64.83% to 69.37%.

The potential underlying reason for the effect of ferritin on cognitive outcomes came when the team detected “an unexpected interaction of ApoE with ferritin.”

They found that CSF ApoE level accounted for 24.3% of the variability in CSF ferritin when tau and Aβ_1–42 were included in the model and 34.1% when they were removed. Moreover, CSF ferritin levels were 22% higher in carriers of the APOE ε4 risk allele than in noncarriers, while CSF ApoE levels were 16% lower.

“That ferritin levels are increased by the APOE-ε4 allele argues that ApoE influences ferritin levels, rather than the reverse”, observe the researchers.

They speculate “that the ε4 genotype raises the baseline iron load of the brain, thus lowering the threshold for iron-mediated neuronal loss in disease.”

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