Alzheimer's disease (AD) brain is marked by severe neuronal death which has been partly attributed to increased oxidative stress. The pathophysiology accounting for this
free radical injury is not well-delineated at this point, but one hypothesis is that a derangement in transition
metal metabolism contributes to the process. We tested the hypothesis that peripheral derangement of transition
metal metabolism is present early in the dementing process. We analyzed non-
heme iron and
copper levels in serum from subjects with normal cognition,
mild cognitive impairment, and early stage
senile dementia and followed these subjects over 5 years. An increase in the ratio of serum
copper to non-
heme iron levels predicted which subjects with
mild cognitive impairment would progress to
dementia versus those that would remain cognitively stable. This increase did not correlate with changes in expression of
iron regulatory protein 2 or selected downstream targets in peripheral lymphocytes. A
cDNA-based microarray (IronChip) containing genes relevant to
iron and
copper metabolism was used to assess transition
metal metabolism in circulating lymphocytes from cognitively normal and demented subjects. No gene was identified as being dysregulated more than 2-fold, and verification using quantitative RT-PCR demonstrated no significant changes in expression for ALAS2, FOS, and CTR1. The increased ratio of serum
copper to serum
iron prior to
dementia has potential as a
biomarker for
cognitive decline and mirrors other changes in serum previously reported by others, but
iron and
copper metabolism pathways appear to be broadly unaffected in peripheral blood in AD.