Download Potential Dangers From Zinc (and Copper

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Potential Dangers From
Zinc (and Copper)
Supplementation:
Implications for Alzheimer
Disease and AMD
A closer look at the data.
BY JERRY RAPP, P H D, AND JEROME SHERMAN, OD
A
lzheimer disease (AD) is an age-related neurodegenerative disease characterized biochemically by
an abnormal buildup of amyloid (A ) protein.1
BACKGROUND ON AD
The divalent cations zinc (Zn++) and copper (Cu++)
have both been associated with the development of
AD. Brain homeostasis of Zn and Cu is severely disrupted in AD.2 An alteration in brain Zn homeostasis,
resulting in either above or below normal levels, has
been implicated in the pathogenesis of senile dementia
characteristic of AD. Excess Zn and Cu at high concentrations seems to promote the neurotoxic effects
of A .3,4 High levels of Zn may generate brain neurotoxicity and neurodegeneration by interfering with
the normal functioning of ligand-gated ion channels.5
Excess Cu contributes to the toxic effects of Zn relating
to the aggregation of A and formation of the amyloid
plaques prevalent in AD.6-8
AD AND AMD
There are similarities between the operative pathological mechanisms in AD and several types of retinal
degenerative disease, including age-related macular
degeneration (AMD).9 It has even been suggested that
retinal changes in AMD may function as a biological
marker for AD diagnosis and progression.9 In addition,
there are data supporting an association between AMD
and cognitive impairment.10
AREDS
Prior to the AREDS (Age-Related Eye Diseases Study)
investigations, the effects of Zn supplementation on the
development and progression of AMD were inconclusive, with some studies showing at least some beneficial
effects,11,12 while other studies showed no association.13-16
The original AREDS investigation (AREDS Report
No. 8)17 demonstrated that high levels of Zn supplementation (80 mg per day—as much as 10 times the recommended dietary allowance, plus 2 mg of Cu) together
with high levels of vitamins C, E, and beta-carotene,
reduced the risk of progression to advanced AMD by 25%
and the risk of moderate vision loss by 19%. The AREDS2
trial lowered the daily dose of Zn for one subgroup of
subjects to 25 mg per day. There was no statistically significant effect on progression to advanced AMD between
the higher dose Zn used in the original AREDS formulation compared to the lower dose Zn used in AREDS2.18
Yet, the National Eye Institute continues to recommend
the high (80 mg) daily dose of Zn.
GENETIC FACTORS
There are currently a total of 19 genomic loci that
have been identified as being potential risk factors in
MAY/JUNE 2014 ADVANCED OCULAR CARE 39
RETINA
the development of AMD.19 The first and probably
most important of these in terms of risk was identified by four independent investigations in 2005 and
involves a single nucleotide polymorphism in complement factor H (CFH).20-23 CFH is a negative modulator
of the alternate complement pathway. This discovery
linked the pathogenesis of AMD to the complement
cascade and its concomitant inflammation.
A more recent article (2008) demonstrated that
high levels of Zn (and copper) cause CFH to aggregate, thereby inhibiting its ability to downregulate the
complement cascade.24 This finding has, in turn, led
to a new hypothesis concerning the effect of Zn on
AMD—that it has opposing roles; specifically that Zn
may be protective at later stages of disease, whereas
it may trigger development of AMD in the disease’s
early stages.25 So, a combination of the previously
mentioned single nucleotide polymorphism in CFH
and the presence of high levels of Zn may inactivate a
key component of the alternate complement pathway
to such an extent that the inflammatory process is
not properly controlled, thereby significantly increasing the risk of developing AMD.
Another gene implicated in AMD is APOE,19 which
codes for apolipoprotein E, a major component of
a specific type of lipoprotein called very-low-density
lipoproteins. Very-low-density lipoproteins remove
excess cholesterol from the blood and carry it to the
liver for processing.
Mutants of both CFH and APOE are also involved
in the development of AD. The same CFH polymorphism, Y402H, that is a major risk factor for AMD is
also associated with AD.26 In addition, both APOE and
Zn are involved in A aggregation and deposition.27
Add to all this the recent study28 which demonstrated that for AMD patients with one or two CFH
risk alleles and no ARMS2 risk alleles, supplementation
with Zn was associated with increased progression to
advanced AMD.
CONCLUSION
With an elderly population of patients already at
risk for both AD and AMD based solely on age, and
with all the aforementioned overlap in biochemical
mechanisms and genetic factors between the two
conditions, is it scientifically reasonable and justifiable
for the NEI to discourage genetic testing for AMD and
to continue to recommend a daily supplement containing a high dose of Zn?
Jerry Rapp, PhD, is a professor, specializing in biochemistry, in the Department of Biological and Vision
40 ADVANCED OCULAR CARE MAY/JUNE 2014
Sciences at SUNY College of Optometry, New York,
New York. He acknowledged no relevant financial
interest. Dr. Rapp may be reached at (212) 938-5786;
[email protected].
Jerome Sherman, OD, is a Distinguished Teaching
Professor at the State University of New York College of
Optometry and in private practice at the Eye Institute
and Laser Center, New York, New York. He acknowledged no relevant financial interest. Dr. Sherman may
be reached at (212) 938-5862; [email protected].
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