An observational study on the influence of the APOE-epsilon 4 allele on the correlation between 'free' copper toxicosis and EEG activity in Alzheimer disease

Since many years the apolipoprotein E epsilon4 allele (APOE-epsilon 4) is known to be associated with Alzheimer disease (AD) but the mechanisms of these associations remained unclear. In the last years, the potential pathogenetic role of 'free' copper (i.e. non-ceruloplasmin bound copper) has been evidenced in AD. Recently, elevated 'free' copper was found to be correlated with slowing of cortical electroencephalographic (EEG) rhythms. The present work aimed to check the hypothesis that the strength of the correlations between free-copper and alterations of cortical rhythms might be different in carriers and non-carriers of the APOE-epsilon 4 allele. Fifty-four AD patients and 20 healthy controls were included in the study. In all of them 1) APOE genotyping was performed; 2) total serum copper and ceruloplasmin was determined in order to calculate the serum 'free' copper; and 3) resting eyes-closed EEG rhythms were recorded and spectral brain activity was estimated via LORETA. A 'two correlation coefficients comparison' test was used to test the strength of the correlation in APOE-epsilon 4 carriers and non-carriers. 'Free' copper levels were higher inpatients than in controls and correlated positively with parietal-temporal delta and negatively with parieto-temporal alpha-1 activities. The correlation between 'free' copper and temporal alpha-1 activity was stronger in APOE-epsilon 4 carriers than in non-carriers. Peroxide levels correlated with higher temporal delta in the AD group. APOE-epsilon 4 appears to modulate the effect of copper on the altered AD brain activities, suggesting that modulation of oxidative stress related to copper dysfunction may be one of the mechanisms that make APOE-epsilon 4 a risk factor for AD. (c) 2008 Elsevier B.V. All rights reserved.