Effect of copper intake on CSF parameters in patients with mild Alzheimer’s disease: a pilot phase 2 clinical trial

Abstract

A plethora of reports suggest that copper (Cu) homeostasis is disturbed in Alzheimer's disease (AD). In the present report we evaluated the efficacy of oral Cu supplementation on CSF biomarkers for AD. In a prospective, randomized, double-blind, placebo-controlled phase 2 clinical trial (12 months long) patients with mild AD received either Cu-(II)-orotate-dihydrate (verum group; 8 mg Cu daily) or placebo (placebo group). The primary outcome measures in CSF were Ab42, Tau and Phospho-Tau. The clinical trial demonstrates that longterm oral intake of 8 mg Cu can be excluded as a risk factor for AD based on CSF biomarker analysis. Cu intake had no effect on the progression of Tau and Phospho-Tau levels in CSF. While Ab42 levels declined by 30% in the placebo group (P = 0.001), they decreased only by 10% (P = 0.04) in the verum group. Since decreased CSF Ab42 is a diagnostic marker for AD, this observation may indicate that Cu treatment had a positive effect on a relevant AD biomarker. Using mini-mental state examination (MMSE) and Alzheimer disease assessment scale-cognitive subscale (ADAS-cog) we have previously demonstrated that there are no Cu treatment effects on cognitive performance, however. Finally, CSF Ab42 levels declined significantly in both groups within 12 months supporting the notion that CSF Ab42 may be valid not only for diagnostic but also for prognostic purposes in AD.

Cognitive tests used in chronic adult human randomised controlled trial micronutrient and phytochemical intervention studies

“…Revealingly, in the remaining eighteen studies (20,24 -26,66,67,69,70,72,74,75,78,82,84,86,89,91,92) , no rationale for task choice was given, although four of these included dementia patients, so task selection was naturally restricted to measures appropriate to these populations (66,70,74,82) .…”

“…Five studies targeted general rather than specific cognition, using only general or 'global' measures of cognitive functions such as the MMSE, the ADAS-Cog and Hasegawa's Dementia Rating Scale (23,66,74,76,82) . Two RCT relied solely on the MMSE or the ADAS-Cog for measurement of cognitive function: one of these studied the effects of flavonoids on Alzheimer's disease patients, showing a significant positive effect of flavonoid treatment over 12 months (23) .…”

“…Five used multivitamins (65 -69) , and two of these also included minerals (67,68) . Ten studies examined vitamin B treatments (70 -79) and three looked at specific minerals: Zn (80) , Fe (81) and Cu (82) . One trialled b-carotene with vitamins C and E (83) .…”

“…Twelve studies (31 %) included participants with MMSE scores of less than 24 out of 30, which is suggestive of cognitive impairment or dementia (23,24,29,66,68,70,71,74,76,82,83,91) . Eighteen studies (46 %) did not screen for cognitive impairment; of these, thirteen included participants over the age of 50 years (19,22,25,27,28,65,69,78,79,84,86,89,90) and may also, therefore, have unwittingly included cognitively impaired participants.…”

“…Overall, the MMSE was used as a performance measure in fourteen RCT (24,28,65,66,68,70 -74,76,82,86,89) but only showed a significant effect of treatment in one (89) , although this may have been due to the inclusion of cognitively impaired controls with a baseline MMSE score of less than 24 out of 30. The ADAS-Cog was used in four studies (23,66,76,82) , and showed significant effects of treatment for patients with a baseline MMSE score of less than 24 in one 12-month flavonoid Alzheimer's disease intervention (23) , with the placebo group showing a significantly greater decline on the ADAS-Cog than the treatment group.…”