Copper dyshomeostasis in Wilson disease and Alzheimer's disease as shown by serum and urine copper indicators.

ABSTRACT

Abnormal handling of copper is the cause of Wilson disease (WD), a rare disorder typified by increased levels in plasma copper not-bound to ceruloplasmin (nCp-Cu, also known as 'free' copper). In Alzheimer's disease (AD), meta-analyses show that copper decreases in brain but increases in serum, due to the nCp Cu component increase. Despite the similarities, a direct comparison of copper biological status in the two diseases has never been carried out. To fill this gap, we evaluated serum copper, ceruloplasmin, nCp-Cu and CuCp in 385 CE and 336 healthy controls previously investigated that were compared with 9 newly diagnosed WD patients. We then assessed 24h copper urinary excretion in 24 WD patients under D-penicillamine (D-pen) treatment and in 35 healthy controls, and compared results with those of AD patients participating to a D-pen phase II clinical trial previously published. After adjusting for sex and age, serum nCp-Cu and CuCp resulted higher in AD and in WD than in healthy controls (both p<0.001). While nCp-Cu was similar between AD and WD, CuCp was higher in WD (p<0.016). 24h urinary copper excretion in AD patients (12.05µg/day) was higher than in healthy controls (4.82µg/day; p<0.001). 77.8% of the AD patients under D-pen treatment had a 24h urinary excretion higher than 200µg/day, suggestive of a failure of copper control. This study provides new insight into the pathophysiology of copper homeostasis in AD, showing a failure of copper control and the CuCp ratio as an eligible marker.