. Ferritin levels in the cerebrospinal fluid predict Alzheimer's disease outcomes and are regulated by APOE. Nat Commun. 2015 May 19;6:6760. PubMed.


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  1. Ayton et al. published interesting data on CSF ferritin as a biomarker for AD. Based on the cognitive data, the authors conclude that ferritin is a trait marker because it correlates cross-sectionally with cognitive scores, but not with change in cognition over time. Still, they also observed that in MCI, baseline ferritin concentrations predicted progression to AD-type dementia, which seems to contradict the first finding. One possible explanation for the discrepancy is that in the first analysis both control and MCI subjects were included. The authors added diagnosis as a factor but did not report that they tested the interaction between diagnosis and change over time; previous studies clearly showed that cognitive change is different between controls and MCI subjects. Hence, it may be possible that a lack of prediction in cognitive change was because the controls improved in cognition at follow-up while MCI subjects declined. Another surprising finding is that ferritin did not differ between diagnostic groups, though it was associated with cognitive scores and also with AD biomarkers that all differ between diagnostic groups. Given the relatively strong correlation of increased ferritin with increased CSF tau and the weak association with increased CSF Aβ42, it may be possible that increased ferritin reflects neurodegeneration rather than an event associated with the onset of the disease. The current evidence seems insufficient to recommend studies on lowering brain iron, but rather emphasizes the need for further cross-sectional and longitudinal studies to define the role of iron in AD.

    The paper of Madeira et al. convincingly shows that D-serine is increased in AD, although the studies, based on CSF, had a relatively small sample size. D-serine correlated with a ratio of CSF Aβ42 and total tau providing additional support for the involvement of D-serine in AD. It would be of interest to see whether D-serine more strongly correlates with CSF tau or CSF Aβ42, as this would give an indication of whether D-serine reflects neuronal injury or amyloid aggregation.

    View all comments by Pieter Jelle Visser
  2. Following a suggestion posted by Pieter Jelle Visser, we have re-analyzed our data (Madeira et al., 2015) to examine individual correlations between CSF D-serine levels and Aβ42/tau/p-tau181 levels in AD and control individuals. The first conclusion from this re-analysis was that there is no correlation between CSF D-serine levels and p-tau181 levels (R2 = 0.0002; P = 0.46). The second conclusion was that there is indeed a negative correlation (R2 = 0.45; P < 0.0001) between CSF D-serine and Aβ42 levels, as might be expected if D-serine is up-regulated and released from neurons and/or glia in response to brain accumulation of Abeta oligomers and amyloid aggregation.

    Intriguingly, however, D-serine levels were positively correlated with total tau levels in the CSF (R2 = 0.37; P = 0.0008), which might indicate that, at least in part, elevation of D-serine in the CSF might be related to neurodegeneration. The overall correlation between the IATI index and D-serine levels that we reported thus appears to originate from both Aβ42 and total tau measures in CSF.

    We note, however, that the sample size used in this study was small. Results were robust when the IATI index was correlated with D-serine levels, but it is possible that the study was insufficiently powered to detect individual correlations between the various analytes in CSF. It will be interesting to further investigate the origin of the D-serine increase in CSF in a future study with a larger cohort of demented and control patients.


    . d-serine levels in Alzheimer's disease: implications for novel biomarker development. Transl Psychiatry. 2015 May 5;5:e561. PubMed.

    View all comments by Mychael Lourenco

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