Patients with increased non-ceruloplasmin copper appear a distinct sub-group of alzheimer's disease: a neuroimaging study

Background: Meta-analyses show that copper non-bound to ceruloplasmin (non-Cp Cu, also known as ‘free’ copper) in serum is higher in a percentage of Alzheimer’s disease (AD) patients. Genetic heterogeneity in AD patients stratified on the basis of non-Cp Cu cut-off sustains the existence of a copper AD metabolic subtype. Objective: In order to find evidence of the existence of a detectable metabolic subtype of AD associated to copper abnormalities, we explore the hypothesis of a neuroimaging pattern heterogeneity in an homogenous and well characterized AD population classified in two groups by the stratification of patients on the basis non-Cp Cu cut-off. Method: We assessed levels of copper, ceruloplasmin, Non-Cp Cu, cerebrospinal levels of total Tau protein (h-tau), Thr 181 phosphorylated tau protein (P-tau) and β-amyloid 1-42, and APOE4 genotype in 66 AD patients and compared neuroimaging indices of a visual rating scale of cerebral atrophy and neurovascular burden in AD patients stratified in ‘Normal’ and ‘High’ non-Cp Cu groups. Results: The stratification for non-Cp Cu originated AD groups which did not differ for medial temporal lobe atrophy, periventricular hyperintensities, deeper hyperintensities (including frontal, parieto-occipital and temporal white matter hyperintensities) infratentorial hyperintensities indices, while they differed for global atrophy. More specifically, AD patients within the high non-Cp Cu group had a less severe burden of global atrophy (p=0.042). Conclusion: This neuroimaging heterogeneity between AD groups is suggestive of the existence of a copper metabolic subtype of AD; Non-Cp Cu appears a good marker of this copper AD.