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, parietooccipital
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.