Intake of copper has no effect on cognition in patients with mild Alzheimer's disease: A pilot phase 2 clinical trial

Article (PDF Available)inJournal of Neural Transmission 115(8):1181-1187 · August 2008with24 Reads
DOI: 10.1007/s00702-008-0080-1 · Source: PubMed
Abstract
Disturbed copper (Cu) homeostasis may be associated with the pathological processes in Alzheimer’s disease (AD). In the present report, we evaluated the efficacy of oral Cu supplementation in the treatment of AD in a prospective, randomized, double-blind, placebo-controlled phase 2 clinical trial in patients with mild AD for 12months. Sixty-eight subjects were randomized. The treatment was well-tolerated. There were however no significant differences in primary outcome measures (Alzheimer’s Disease Assessment Scale, Cognitive subscale, Mini Mental Status Examination) between the verum [Cu-(II)-orotate-dihydrate; 8mg Cu daily] and the placebo group. Despite a number of findings supporting the hypothesis of environmental Cu modulating AD, our results demonstrate that oral Cu intake has neither a detrimental nor a promoting effect on the progression of AD.
ALZHEIMER’S DISEASE AND RELATED DISORDERS - ORIGINAL ARTICLE
Intake of copper has no effect on cognition in patients with mild
Alzheimer’s disease: a pilot phase 2 clinical trial
Holger Kessler Æ Thomas A. Bayer Æ Daniela Bach Æ Thomas Schneider-Axmann Æ
Tillmann Supprian Æ Wolfgang Herrmann Æ Manfred Haber Æ Gerd Multhaup Æ
Peter Falkai Æ Frank-Gerald Pajonk
Received: 18 March 2008 / Accepted: 5 June 2008 / Published online: 28 June 2008
Ó The Author(s) 2008
Abstract Disturbed copper (Cu) homeostasis may be
associated with the pathological processes in Alzheimer’s
disease (AD). In the present report, we evaluated the effi-
cacy of oral Cu supplementation in the treatment of AD in
a prospective, randomized, double-blind, placebo-con-
trolled phase 2 clinical trial in patients with mild AD for
12 months. Sixty-eight subjects were randomized. The
treatment was well-tolerated. There were however no sig-
nificant differences in primary outcome measures
(Alzheimer’s Disease Assessment Scale, Cognitive sub-
scale, Mini Mental Status Examination) between the verum
[Cu-(II)-orotate-dihydrate; 8 mg Cu daily] and the placebo
group. Despite a number of findings supporting the
hypothesis of environmental Cu modulating AD, our
results demonstrate that oral Cu intake has neither a det-
rimental nor a promoting effect on the progression of AD.
Keywords Cu Alzheimer Clinical trial ADAS-cog
MMSE
Abbreviations
AAS Atomic absorption spectroscopy
Ab Amyloid beta peptide
AD Alzheimer’s disease
ADAS-cog Alzheimer’s disease assessment scale,
cognitive subscale
ADRDA Alzheimer’s disease and related disorders
association
APP Amyloid precursor protein
CDT Clock drawing test
Cu Copper
CuBD Copper binding domain
MMSE Mini mental status examination
NINCDS National Institute of Neurological
and Communicative Disorders and Stroke
SOD-1 Superoxide dismutase-1
Zn Zinc
Introduction
Alzheimer’s disease (AD) is a progressive neurodegener-
ative disease characterized by extracellular deposition of
Holger Kessler, Thomas A. Bayer and Daniela Bach have contributed
equally.
H. Kessler D. Bach
Department of Psychiatry and Psychotherapy,
Saarland University Hospital, Homburg/Saar, Germany
T. A. Bayer (&) T. Schneider-Axmann P. Falkai
Division of Molecular Psychiatry, Department of Psychiatry
and Psychotherapy, University of Go
¨
ttingen,
von-Siebold-Strasse 5, 37075 Go
¨
ttingen, Germany
e-mail: tbayer@gwdg.de
T. Supprian
Department of Geriatric Psychiatry, Rheinische Kliniken
Du
¨
sseldorf, Dusseldorf, Germany
W. Herrmann
Central Laboratory, Department for Clinical Chemistry,
Saarland University Hospital, Homburg/Saar, Germany
M. Haber
Central Pharmacy, Saarland University Hospital,
Homburg/Saar, Germany
G. Multhaup
Institute for Chemistry and Biochemistry, Free University,
Berlin, Germany
F.-G. Pajonk
Center for Psychiatric and Psychotherapeutic Care
and Rehabilitation, Dr. K. Fontheim’s Hospital
for Mental Health, Liebenburg, Germany
123
J Neural Transm (2008) 115:1181–1187
DOI 10.1007/s00702-008-0080-1
Ab peptides in senile plaques and intracellular accumula-
tion of hyperphosphorylated s protein in neuronal cells as
neurofibrillary tangles.
Potentially toxic Ab peptides are generated from the
copper-binding amyloid precursor protein (APP) by two
independent proteolytic events (Bayer et al. 2001; Glenner
and Wong 1984; Hesse et al. 1994; Kang et al. 1987). APP
is actively involved in balancing Cu concentrations in cells.
In APP-knock-out mice, Cu levels were found increased in
cerebral cortex and liver (White et al. 1999), whereas
overexpression of APP was reported to result in signifi-
cantly reduced Cu levels in brain tissue of different APP
transgenic mouse strains (Bayer et al. 2003; Phinney et al.
2003) and in mice overexpressing the C-terminal fragment
of APP (and enhanced Ab secretion) (Maynard et al. 2002).
The N-terminal Cu binding domain (CuBD-I) of APP
shows structural homology to the Cu binding domain of Cu
chaperons (Barnham et al. 2003) binding Cu with nano-
molar affinity (Hesse et al. 1994). A secondary CuBD-II
appears in Ab after its release from APP (Atwood et al.
2000), and Cu application was reported to increase Ab
aggregation in vitro [reviewed in (Bush 2003)]. APP
reduces Cu (II) to Cu (I), leading to oxidative modification
of APP (Multhaup et al. 1996), which is facilitated through
the protein surface localization of the binding site thus
resembling so-called cytoplasmic Cu chaperones (Barnham
et al. 2003).
In cell culture systems, Cu supplementation was found
to stimulate the non-amyloidogenic APP pathway thereby
suppressing the formation of b amyloid (Borchardt et al.
1999). More recently, APP was shown in yeast cells to
have a Cu efflux activity thereby explaining why APP
overexpressing mice have a reduced Cu level in their
brains (Bayer et al. 2003; Phinney et al. 2003; Treiber
et al. 2004).
In the brain, APP transgenic mice have not only lower
Cu levels but they also exhibit a reduced Cu, Zn superoxide
dismutase-1 (SOD-1) activity compared to wild-type mice.
Dietary Cu supplementation in a transgenic mouse model
for AD increased bioavailable brain Cu levels, restored
SOD-1 activity, prevented premature death and decreased
Ab levels (Bayer et al. 2003). In Wilson’s disease, a
mutation of copper ATPase 7B leads to Cu accumulation in
the liver and a threefold to fourfold higher Cu level in the
brain. After crossbreeding of APP transgenic mice with so-
called toxic milk mice having a defect in the copper
ATPase 7B it was observed that APP-related lethality
could be rescued. In addition, Ab levels were significantly
reduced due to the genetically upregulated Cu level
(Phinney et al. 2003).
Earlier studies in animals have reported that elevated Cu
is a risk factor for developing the AD related pathology.
Cherny et al. (2001) showed that clioquinol, a copper and
zinc chelating agent, can remove b amyloid plaque
pathology. However, it was unclear how this effect worked,
since the authors reported an increase of soluble Cu and Zn
levels in the brain of treated mice. This apparently con-
tradictory finding could be explained by the finding that
clioquinol mediates Cu uptake by transporting Cu across
cell membranes counteracting Cu efflux activities of APP
(Treiber et al. 2004).
Normally, Cu contained in the food is taken up in the
stomach and then absorbed in the small intestine. About
30–50% of the Cu is absorbed. Cu is distributed from the
liver throughout the body and transported in the blood-
stream bound to ceruloplasmin. The liver is the most
important organ for Cu distribution and storage. Cu is
excreted via the biliary system. Usually, 2 mg of Cu per
day are taken with food. Ingestion of as much as 10 mg of
Cu per day is considered to be safe. The clinical reference
value for physiological Cu plasma concentrations is
65–165 lg/dl [reviewed in (Kessler et al. 2005)].
Since increased Cu levels reduced Ab production in
APP transgenic mouse models, we speculated that Cu
intake stabilizes cognitive decline in AD patients. Thus,
we treated AD patients with supplemental Cu and moni-
tored the progression of the disease by recording the
cognitive performance for 12 months using neuropsy-
chological tests.
Material and methods
Study population
Criteria for participation in the study included written
informed consent as well as caregiver consent, a diagnosis
of probable AD by means of NINCDS-ADRDA criteria
(McKhann et al. 1984), a Mini Mental Status Examination
score \25, and receipt of a 5–10 mg dose of donepezil for
at least 2 months. All patients continued to receive do-
nepezil during the study. To be enrolled in the study
patients had to be 50–80 years of age and not able to bear
children. Patients with severe and unstable somatic dis-
eases and patients with present or known history of
alcohol, drug or medication abuse were excluded. Patients
taking drugs for coexistent diseases were included except
those taking psychotropic drugs, ‘nootropics’ or health
food supplements. The trial has been approved by the
appropriate ethics committee and has therefore been per-
formed in accordance with the ethical standards laid down
in the 1964 Declaration of Helsinki. All persons gave
their informed consent prior to their inclusion in the
study.
1182 H. Kessler et al.
123
Study design
The study had a monocenter, prospective, double-blind,
placebo-controlled, parallel-group randomized design.
Sixty-eight patients were recruited. Patients were randomly
allocated either to placebo or to verum (Cu orotate). The
oral dosage of Cu-(II)-orotate-dihydrate was 51.62 mg
(corresponding to 8 mg Cu) once daily. To maintain
blinding, capsules containing Cu orotate and placebo had
identical shape and color. The duration of the study was
12 months. The study was registered at www.clinicaltri-
als.gov with the identification number NCT00608946.
Study procedures
Screening procedures consisted of a medical history, phys-
ical examination and psychometric tests. Blood was
collected to determine the level of Cu and zinc by using
atomic absorption spectroscopy (AAS). Furthermore, blood
count included liver enzymes and anti-mitochondrial anti-
bodies (for exclusion of cholestatic liver diseases). Atomic
absorption spectroscopy: Blood samples were collected into
metal-free tubes that contained lithium heparin as an anti-
coagulant. Concentrations of Cu were measured in lithium-
heparin plasma samples, utilizing flame AAS (Perkin Elmer,
AAnalyst 800). Samples were diluted with deionized water
and the analysis was performed against standards prepared
in glycerol to approximate the viscosity characteristics of the
diluted samples. Standard atomic absorption conditions
were utilized for Cu (air acetylene, wave length 324.8 nm).
Outcome measures
The primary efficacy variables were the changes from the
baseline score on the cognitive subscale of the Alzheimer’s
Disease Assessment Scale (ADAS-cog) and on the MMSE.
Efficacy evaluations were performed at baseline and at
month 3, 6, 9 and 12.
Therapeutic drug monitoring
Plasma Cu levels were measured at every visit (at baseline
and at month 3, 6, 9 and 12).
Safety measures
Standard adverse event reporting was conducted. Before
baseline, the Cu content in drinking water at the patients’
home was analyzed under standard conditions; concentra-
tion of Cu in drinking water must not exceed 2 mg/l. For
safety reasons, blood analyses (including especially plasma
Cu levels and liver enzymes) were performed at week 1, 2,
3 and 4 after baseline and at month 3, 6, 9 and 12.
Data analysis
Evidence of efficacy was indicated by a significant differ-
ence in change from baseline between treatment arms. For
statistical analyses SPSS 14 was used. All tests were two-
tailed. Demographic variables, data on the course of the
disease and clinical data at baseline of the patients that
completed the examinations were compared between the
verum and the placebo group with one-way analysis of
variance (ANOVA). Chi-square test on independence was
used to analyze, if the distribution of sex was different
between the two groups. Dependent variables were the
ADAS-cog total score and the MMSE score at baseline (t
0
)
and at four following measurements with intervals of
3 months each (t
3
, t
6
, t
9
, t
12
). Furthermore, plasma Cu levels
at the beginning (t
0
) and at the end (t
12
) of the study were
compared. Independent between-subject factor was treat-
ment group (placebo, verum), within-subject factor was
time of measurement. For ADAS-cog, MMSE and plasma
copper the differences between the values at the end (t
12
)
and at the beginning of the study (t
0
) were computed as
measures for the changes over time. Pearson’s product
moment correlations between these differences and inter-
vening variables age, disease duration, age at onset of the
disease and duration of education were calculated, intend-
ing to analyze, if these variables show a significant
influence on the changes of the dependent variables.
ANOVA with between-subject factors treatment group and
gender was use to analyze, if the changes were gender-
related. For the dependent variables Kolmogorov–Smirnov
tests were used to test, if there were significant deviations
from the normality assumption. The results of these pre-
liminary statistics regulated the main analysis. The basic
hypotheses were that the dependent variables ADAS-cog
and MMSE change continuously over time and that these
changes are different between the placebo and the verum
group. The third hypothesis was that plasma copper level
increases over time in the verum, but not in the placebo
group. To analyze these hypotheses, the general linear
model procedure was used to perform multivariate analyses
of variance (MANOVA) with repeated measures design.
Within-subject factor was time of measurement between-
subject factor was treatment group. Since there was no
significant influence of the intervening variables sex, age,
disease duration, age at onset of the disease and duration of
education on the differences of the dependent variables
between the values at the end and at the beginning of the
study, no additional covariates or factors were entered to the
model in the main analysis. In the repeated measures
analyses MANOVA performed an orthonormal transfor-
mation of the dependent variables. The Mauchly test of
sphericity was used to test the assumption that the covari-
ance matrix of the transformed orthonormal variables was
Effect of copper on cognition in patients with mild Alzheimer’s disease 1183
123
constant on the diagonal and zero off the diagonal. This was
the case, if the values of the dependent variables show the
same error and interaction effects at each measure time. If
the sphericity assumption was violated, the Greenhouse–
Geisser epsilon correction was applied.
Results
Subject recruitment and demographics
The randomization of patients and their progress through
the study is summarized in Fig. 1. A total of 120 patients
were screened; 52 of these patients were excluded due to
exclusion criteria. Altogether 68 subjects were randomized,
with 33 patients receiving placebo and 35 patients receiv-
ing Cu. There were no significant mean differences for age,
disease duration, age at onset of the disease, education and
clock drawing test at baseline between the verum and the
placebo patients. The sex distribution was not significantly
different between the two treatment groups (for details
see Table 1). For the total verum and placebo group there
were no significant correlations between the intervening
variables age, disease duration, age at onset of the dis-
ease, duration of education and the changes over time for
ADAS cog (t
12
- t
0
), MMSE (t
12
- t
0
) and plasma copper
(t
12
- t
0
). From ANOVA with factors group and gender
there were no significant gender effects on the changes of
the dependent variables over time. Therefore, no inter-
vening variables had to be entered to the model in the main
analysis. For all dependent variables, Kolmogorov–
Smirnov tests did show no significant deviations from
normality assumption.
Proof of concept
For the ADAS-cog score, an increase of the scores over
time was observed in the placebo group (t
12
vs. t
0
:
+15.5%) and in the verum group (t
12
vs. t
0
: +8.8%). From
MANOVA with the repeated measures design there were
significant effects of within-subject factor time (df = 3.3,
177.1; F = 3.1; P = 0.023) and of between-subject factor
treatment group (df = 1, 53; F = 4.7; P = 0.034) pointing
out generally lower values in the verum group. However,
there was no significant time 9 treatment group interaction
(df = 3.3, 177.1; F = 0.4; P = 0.78) (Fig. 2a).
The MMSE score, a less sensitive measure of cognitive
impairment, showed a similar pattern. There was a
decrease over time in both treatment groups (t
12
vs. t
0
:
placebo: -9.5%, verum: -10.5%). The MANOVA
Fig. 1 Outline of flowchart of subjects studied. SAE serious adverse event
1184 H. Kessler et al.
123
repeated measures analysis resulted in significant effects of
within-subject factor time (df = 3.2, 173.8; F = 9.5;
P \ 0.0005). Effects of between-subject factor treatment
group were not significant (df = 1, 54; F = 1.6;
P = 0.21), and there was no significant interaction between
time and treatment group (df = 3.2, 173.8; F = 0.2;
P = 0.88) (Fig. 2b).
Altogether, cognitive abilities worsened progressively in
AD patients receiving Cu as well as in those patients taking
placebo. Differences between the two groups in the mean
change from baseline scores were not statistically signifi-
cant at any visit.
Plasma levels of copper
In both groups, mean absolute levels of Cu at baseline were
within the age-related normative range. From MANOVA
repeated measures analysis for plasma copper there were no
significant mean differences for within-subject factor time
(df = 1, 50; F = 1.7; P = 0.20) and no significant effects
for between-factor treatment group (df = 1, 50; F = 1.1;
P = 0.29), while the time 9 treatment group interaction
was significant (df = 1, 50; F = 5.2; P = 0.027), as mean
plasma Cu was decreased over time in the placebo group
(t
12
vs. t
0
: t
12
mean ± SD = 98.5 ± 17.7 lg/dl and
t
0
mean ± SD = 109 ± 23.4 lg/dl; -7.5%), but stabilized
in the verum group (t
12
vs. t
0
: t
12
mean ± SD = 100.8 ±
21.6 lg/dl and t
0
mean ± SD = 100.7 ± 15.3 lg/dl;
+2.3%). No treatment effect was however observed on Zn
and ceruloplasmin levels (not shown).
Safety results and analysis
Safety analysis was conducted on all data irrespective of the
stage reached in the trial. In the placebo group, 28 patients
(84.5%) continued taking part until the end of the study, in
the verum group 29 patients (82.9%) completed treatment.
From the Chi-square test on independence, the drop-out rate
was not statistically different between the two groups
(v
2
= 0.05, P = 0.82). Six patients discontinued the
treatment in the Cu group: one withdrew consent, three due
to adverse events, one due to non-compliance and one
patient for other reasons. The mentioned drop-outs related to
serious adverse events were hospitalizations due to intra-
cranial hemorrhage (1 patient), diagnosis of non-Hodgkin
Table 1 Demographic and clinical data at baseline of the patients that completed the study
Sex (no. of males; no. of females) Placebo (n = 28) Verum (n = 29) df v
2
P
m: 10; f:18 m: 15; f: 14 1 1.48 0.23
Mean ± SD Mean ± SD df F P
Age (years) 69.4 ± 8.1 69.6 ± 6.6 1, 55 0.01 0.94
Disease duration (months) 25.2 ± 16.2 34.0 ± 31.2 1, 54 1.76 0.19
Age at onset (years) 67.4 ± 7.9 66.6 ± 6.1 1, 54 0.17 0.68
Education (years) 10.6 ± 1.9 11.6 ± 2.9 1, 54 2.28 0.14
CDT (scores) 2.8 ± 1.3 2.8 ± 1.2 1, 55 0.01 0.93
n Number of cases, SD standard deviation, no. number, FFstatistics, v
2
v
2
statistics, P error probability for falsely rejecting the null hypothesis,
that there are no mean differences between the treatment groups
Fig. 2 Mean and standard deviation change in cognitive abilities.
a Cognitive abilities assessed with ADAS-cog in Cu (verum) vs.
placebo arms. b Cognitive abilities assessed with MMSE score in Cu
(verum) vs. placebo arms
Effect of copper on cognition in patients with mild Alzheimer’s disease 1185
123
lymphoma (1 patient) and suspected cerebral infarction
(1 patient). None of the serious adverse events leading to
discontinuation of the study was considered to be attribut-
able to Cu supplementation. Five patients discontinued the
participation in the placebo group. No serious adverse
events leading to discontinuation were recorded in the pla-
cebo group. Three patients withdrew their consent, one
failed to return and one discontinued for other reasons. The
liver status and hematological characteristics of the patients
was monitored at all visits. No significant changes were
detected at any time as an effect of Cu treatment.
Altogether, the study medication was well-tolerated.
There were no obvious overall trends or clinically relevant
differences between the two groups in vital signs, physical
examination, hematological characteristics or biochemical
analyses.
Discussion
There is increasing evidence that the metalloproteins APP
and Ab are both involved in brain Cu homeostasis. May-
nard et al. (2002) have shown that overexpression of the
carboxy-terminal fragment of APP elicits significantly
reduced Cu levels in transgenic mouse brain. In addition,
overexpression of APP in three different lines of APP
transgenic mice resulted in significantly reduced Cu levels
(Bayer et al. 2003; Maynard et al. 2002; Phinney et al.
2003). This effect might be further enhanced by the
reduced bioavailability of Cu due to the accumulation of
high amounts of Cu in plaques (Lovell et al. 1998). The
APP mediated Cu efflux activity observed in APP over-
expressing living cells may also explain Cu deficiency and
a subsequently reduced SOD-1 activity. Remarkably, the
TxJ mutation of the toxic milk mouse (mutation in the
Wilson’s disease gene) with a genetically 1.5-fold upreg-
ulated Cu level was associated with an increased survival
of APP transgenic mice and lowered endogenous murine
Ab levels prior to detectable Ab plaques formed by the
human APP transgene. The CuATPase7b transporter is a P-
type ATPase associated with the trans Golgi network.
These observations were the basis to hypothesize that
restoring brain Cu homeostasis might have a beneficial
influence on the progression of AD.
In the present clinical trial, we demonstrate that oral
intake of Cu orotate (8 mg Cu daily for 12 months) has no
effect on cognitive abilities of AD patients and is neither
detrimental nor beneficial. The treatment was generally
well-tolerated. The plasma Cu levels declined in the pla-
cebo group during the 12 months-period. Such a decline
was not observed in the Cu-treated group. Although the
placebo group had higher Cu levels as compared to the
verum group at the beginning of the study this effect is of
interest. However, this observation should be taken with
caution, because the statistical significance is rather weak.
The analysis of CSF Cu showed that the Cu levels were
stabilized only in the Cu-treated group. This observation
indicates that oral Cu intake can modulate CSF Cu levels
and antagonizes the age-related increase of Cu levels
hypothetically by activating the homeostatic system, i.e.,
balancing the uptake and excretion pathways (H. Kessler
et al., in preparation).
These observations are in good agreement with signifi-
cantly lower levels of blood Cu in those AD patients, who
fulfilled the criteria of CSF diagnosis for AD, i.e., at least
two of the three markers (Ab42, Tau, Phospho-Tau) were
out of the reference range (Kessler et al. 2006). In addition,
we demonstrated reduced Cu levels in blood in patients
with higher ADAS-cog scores (making more mistakes in
this neuropsychological test) (Pajonk et al. 2005), i.e., AD
progression is associated with lower Cu levels in blood.
One animal study showed that treatment of 21-months-
old Tg2576 mice with clioquinol, a Cu–Zn chelator,
inhibited plaque formation and concomitantly increased
soluble brain Cu and Zn levels (Cherny et al. 2001). This
increase of Cu- and Zn-ions might either be attributed to an
inefficiency of the chelator with its known weak affinities
for Zn (K1 = 7.0) and for Cu (K1 = 8.9) or even more
likely, due to a facilitated uptake in brain of clioquinol–Cu
complexes. The latter hypothesis has been experimentally
confirmed in vitro (Treiber et al. 2004). Moreover, lowered
insoluble Ab levels (by 49%) and increased soluble Ab
levels (by 50%) were accompanied with elevated Cu levels
(and Zn).
When AD patients were treated with clioquinol, the
placebo group deteriorated faster than the clioquinol group
suggesting a beneficial effect upon clioquinol treatment
(Ritchie et al. 2003). This could be due to clioquinol
mediating Cu uptake into the cell or the metal-protein-
attenuating-compunds properties. In APP transgenic mice
Cu supplementation abrogated this clioquinol effect and
rescued premature death (Schafer et al. 2007).
Postmortem Cu levels in CNS of AD patients were
found to be decreased (Deibel et al. 1996) or unchanged
(Loeffler et al. 1996). Controversial results have also been
published on the level of Cu in plasma, plasma and brain in
AD patients. Plasma Cu levels being within the normal
range in AD patients is in good agreement with an earlier
study (Jeandel et al. 1989). However, other studies suggest
that elevated Cu levels are a risk factor for AD (Squitti
et al. 2002, 2003, 2004).
Short-term high Cu intake has been reported not to
affect Cu status or functions related to Cu status, only long-
term high Cu intake can result in increases in some
parameters in young men (Turnlund et al. 2004). Our study
is in good agreement with this report adding further
1186 H. Kessler et al.
123
evidence that long-term intake of Cu stabilizes Cu levels in
plasma.
The present clinical trial demonstrates that (1) long-term
oral intake of 8 mg Cu can be excluded as a risk factor for
AD. (2) Long-term oral intake of Cu is well-tolerated by
AD patients. (3) Cu intake has no effect on the progression
of AD.
Acknowledgments The excellent technical help of Patricia Nagel,
Katrin Rubly, Stephanie Schaefer, Oliver Wirths, Karl-Heinz Hoff-
mann and Irene Witzmann is gratefully acknowledged. Financial
support was provided by the HOMFOR program of the Saarland
University Medical Faculty and the International Copper Association.
This work has been supported in part by the International Copper
Association (to Thomas A. Bayer) and Saarland University (HOM-
FOR program to Frank-Gerald Pajonk). The authors report no
conflicts of interest. We have full control of all primary data and agree
to allow the journal to review their data if requested.
Open Access This article is distributed under the terms of the
Creative Commons Attribution Noncommercial License which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are credited.
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    • "We do not recommend the use of copper supplements for prevention or correction of cognitive decline. (Grade of evidence: very low) Commentary: In a RCT of low methodological rigor [160] 68 people with dementia were randomized to receive copper or placebo. During the 12 month follow-up the worsening in cognitive function was similar in the intervention and placebo group. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Older people suffering from dementia are at increased risk of malnutrition due to various nutritional problems, and the question arises which interventions are effective in maintaining adequate nutritional intake and nutritional status in the course of the disease. It is of further interest whether supplementation of energy and/or specific nutrients is able to prevent further cognitive decline or even correct cognitive impairment, and in which situations artificial nutritional support is justified. Objective: It is the purpose of these guidelines to cover these issues with evidence-based recommendations. Methods: The guidelines were developed by an international multidisciplinary working group in accordance with officially accepted standards. The GRADE system was used for assigning strength of evidence. Recommendations were discussed, submitted to Delphi rounds and accepted in an online survey among ESPEN members. Results: 26 recommendations for nutritional care of older persons with dementia are given. In every person with dementia, screening for malnutrition and close monitoring of body weight are recommended. In all stages of the disease, oral nutrition may be supported by provision of adequate, attractive food in a pleasant environment, by adequate nursing support and elimination of potential causes of malnutrition. Supplementation of single nutrients is not recommended unless there is a sign of deficiency. Oral nutritional supplements are recommended to improve nutritional status but not to correct cognitive impairment or prevent cognitive decline. Artificial nutrition is suggested in patients with mild or moderate dementia for a limited period of time to overcome a crisis situation with markedly insufficient oral intake, if low nutritional intake is predominantly caused by a potentially reversible condition, but not in patients with severe dementia or in the terminal phase of life. Conclusion: Nutritional care and support should be an integral part of dementia management. In all stages of the disease, the decision for or against nutritional interventions should be made on an individual basis after carefully balancing expected benefit and potential burden, taking the (assumed) patient will and general prognosis into account.
    Article · Sep 2015
    • "However, this hypothesis is not well thought out, since AD patients display none of the manifestations of copper deficiency, which are a very low serum copper, anemia and bone marrow depression, and myelopolyneuropathy neurologic syndrome. Another example is Kessler et al. (2008) who gave copper to AD patients, and claimed to see no worsening. They saw no improvement either, which disproved their hypothesis that patients were suffering from copper deficiency. "
    [Show abstract] [Hide abstract] ABSTRACT: Evidence will be presented that the Alzheimer's disease (AD) epidemic is new, the disease being very rare in the 1900s. The incidence is increasing rapidly, but only in developed countries. We postulate that the new emerging environmental factor partially causal of the AD epidemic is ingestion of inorganic copper from drinking water and taking supplement pills, along with a high fat diet. Inorganic copper can be partially directly absorbed and elevate the serum free copper pool. The Squitti group has shown that serum free copper is elevated in AD, correlates with cognition, and predicts cognition loss. Thus, our inorganic copper hypothesis fits well with the Squitti group data. We have also shown that AD patients are zinc deficient compared to age-matched controls. Because zinc is a neuronal protective factor, we postulate that zinc deficiency may also be partially causative of AD. We carried out a small 6 month double blind study of a new zinc formulation and found that in patients age 70 and over, it protected against cognition loss. Zinc therapy also significantly reduced serum free copper in AD patients, so efficacy may come from restoring normal zinc levels, or from lowering serum free copper, or from both.
    Full-text · Article · May 2014
    • "). Moreover, the supplementation of an oral therapy of copper to subjects with AD in a phase 2, proof of concept, clinical trial by Kessler et al., 2008 was unsuccessful [57]. Conversely , an extensive number of studies since 1990 demonstrated that the hypermetallation of amyloid-␤ peptides can cause oxidative stress, H 2 O 2 production, and A␤ plaques (reviewed in [56]). "
    [Show abstract] [Hide abstract] ABSTRACT: The fraction of copper not bound to ceruloplasmin seems altered in Alzheimer's disease (AD). We have addressed this notion evaluating all the studies carried out from 1996 until March 2013 by means of meta-analysis. We performed our analysis on diverse indices evaluating the relationship between copper and ceruloplasmin in general circulation, namely 'Non-Cp copper', '% Non-Cp copper', and 'Adjusted copper'. For Non-Cp copper and % Non-Cp copper, the correct stoichiometry between copper and ceruloplasmin (6-8 atoms of copper for each ceruloplasmin molecule) in healthy controls has been adopted as criterion for the study to be included in the meta-analysis evaluating data with the canonic Walshe's formula for Non-Cp copper. Copper to ceruloplasmin ratio (Cu:Cp), which is an internal quality control check for ceruloplasmin calibration, was used as an index of the actual stoichiometry in the specimens. Adjusted (Adj-Cp) copper, even though less reliable, was calculated, allowing the evaluation of all the studies selected. An additional meta-analysis of systemic total copper was re-calculated accounting for all the studies carried out from 1983 to March 2013. Ten studies were analyzed in the meta-analysis for Non-Cp copper and % Non-Cp copper reaching a pooled total of 599 AD subjects and 867 controls. For Adj-Cp copper, 14 studies were analyzed with a pooled total of 879 AD and 1,712 controls. 27 studies were considered for systemic total copper meta-analysis, with a pooled total of 1,393 AD and 2,159 controls. All the copper indices analyzed were significantly higher in AD subjects compared to healthy controls.
    Full-text · Article · Sep 2013
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