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2012 study: Zinc supplementation improves cognition in Alzheimer's Disease
Posted: Friday, October 5, 2012 2:54 PM
Joined: 12/20/2011
Posts: 217


Found this interesting:

Copper excess, zinc deficiency, and cognition loss in Alzheimer's disease


George J. Brewer

Article first published online: 22 MAR 2012

DOI: 10.1002/biof.1005


In this special issue about biofactors causing cognitive impairment, we present evidence for and discuss two such biofactors.

One is excess copper, causing neuronal toxicity.

The other is zinc deficiency, causing neuronal damage.

We present evidence that Alzheimer's disease (AD) has become an epidemic in developed, but not undeveloped, countries and that the epidemic is a new disease phenomenon, beginning in the early 1900s and exploding in the last 50 years.

This leads to the conclusion that something in the developed environment is a major risk factor for AD.

We hypothesize that the factor is inorganic copper, leached from the copper plumbing, the use of which coincides with the AD epidemic.

We present a web of evidence supporting this hypothesis.

Regarding zinc, we have shown that patients with AD are zinc deficient when compared with age-matched controls.

Zinc has critical functions in the brain, and lack of zinc can cause neuronal death.

A nonblinded study about 20 years ago showed considerable improvement in AD with zinc therapy, and a mouse AD model study also showed significant cognitive benefit from zinc supplementation.

In a small blinded study we carried out, post hoc analysis revealed that
6 months of zinc therapy resulted in significant benefit relative to placebo controls in two cognitive measuring systems.

These two factors may be linked in that zinc therapy significantly reduced free copper levels.

Thus, zinc may act by lowering copper toxicity or by direct benefit on neuronal health, or both.



This other, recent review says the evidence from other studies is inconclusive about whether zinc supplementation can help:

Zinc diet and Alzheimer's disease: A systematic review 

Posted: Friday, October 5, 2012 5:56 PM
Joined: 12/20/2011
Posts: 217



Here's much more from the author of the above study, George J. Brewer.  He discusses his copper hypothesis of Alzheimer's disease and responds to arguments that have been raised against it:

Issues Raised Involving the Copper Hypotheses in the Causation of Alzheimer's Disease

Also see:

The Risks of Copper Toxicity Contributing to Cognitive Decline in the Aging Population and to Alzheimer's Disease 


Here's just a very tiny study:

"... ten patients with Alzheimer's disease were given 27 mg of Zinc (as Zinc aspartate) daily. Only two patients failed to show improvement in memory, understanding, communication, and social contact. In one seventy-nine-year-old patient, the response was labeled 'unbelievable' by both medical staff and family."
- Michael T. Murray, N.D., Joseph E. Pizzorno, N.D., Encyclopedia or Natural Medicine, Revised Second Edition 

And also see:

Does Zinc Help the Brain With Memory? 

Posted: Saturday, October 6, 2012 12:15 PM
Joined: 12/20/2011
Posts: 217


Adeona's Pharmaceuticals' reaZin zinc tablet, which I think is zinc cysteine, failed to help much in a recent trial. 

Possibly zinc aspartate (mentioned above in that tiny, very successful trial) and other forms of zinc may work better.

At this point I don't know exactly what forms of zinc were used in the other trials that claimed cognitive improvement.

Lane Simonian
Posted: Saturday, October 6, 2012 1:24 PM
Joined: 12/12/2011
Posts: 4854

This may be part of it, Onward, as the cysteine transporter is rendered ineffective in Alzheimer's disease due to oxidation.  The other part may be timing.  As your other post pointed out, some researchers believe that copper and zinc contribute to the aggregation of plaques.  While the plaques are aggregating supplementation with zinc may not be advisable.  But when the aggregation slows down, zinc supplementation may help lower levels of homocysteine and increase superoxide dismutase activity both of which would in turn lower levels of peroxynitrites--the true culprit in Alzheimer's disease.  This strategy may be somewhat more effective that trying to chelate the zinc out of the plaques.   

Posted: Saturday, October 6, 2012 2:42 PM
Joined: 12/21/2011
Posts: 62

Important is also conversion of 5-htp to serotonin which needs:

- vit. C, B6, Zinc, Magnesium.

Serotonin is responsible for many important things like mood and sleep. Serotonin inhibits/controls dopamine and is a component of reaction which creates melatonin.

Posted: Sunday, October 7, 2012 7:52 PM
Joined: 12/20/2011
Posts: 217

Lane and Tom(ek), I appreciate your input. 



Lane Simonian wrote:

This may be part of it, Onward, as the cysteine transporter is rendered ineffective in Alzheimer's disease due to oxidation.  The other part may be timing.  As your other post pointed out, some researchers believe that copper and zinc contribute to the aggregation of plaques.  While the plaques are aggregating supplementation with zinc may not be advisable.  But when the aggregation slows down, zinc supplementation may help lower levels of homocysteine and increase superoxide dismutase activity both of which would in turn lower levels of peroxynitrites--the true culprit in Alzheimer's disease.  This strategy may be somewhat more effective that trying to chelate the zinc out of the plaques.   

Lane, here's a recent, relevant comment from George J. Brewer that might be of interest.  It's about his view of the relationship between zinc and the Alzheimer's plaques.  He views inorganic copper as the bad guy, and zinc as the good guy: 



Issues Raised Involving the Copper Hypotheses in the Causation of Alzheimer's Disease

George J. Brewer 


...  One of the hallmarks of AD pathology in the brain is extracellular amyloid plaques [3]. These are polymers of beta amyloid, a polypeptide clipped off the end of the amyloid precursor protein. The amyloid plaques are thought to be toxic to neurons and are thought to be an integral part of the pathogenesis of AD. These plaques are very rich in copper and zinc, and for a time it was thought both elements were involved in plaque formation [4, 5]. However, it now seems likely that copper is required for plaque formation while zinc is simply bound in large amounts to the plaques. Indeed the plaques, representing a sink for zinc, may add harmful depletion of zinc in the brain [6]. It is already known, based on serum zinc levels, that AD patients are zinc deficient [7], and zinc plays important roles in neuronal function. Thus, copper may be incriminated as a toxic agent, while zinc may be protective, and the brain zinc deficient. Copper also contributes to generation of toxic oxygen radicals in interaction with amyloid plaques [8]. These roles make extracellular copper a potential culprit in the pathogenesis of AD...

[Here are the relevant footnotes:]

3. W. Mally and P. Caldwell, Alzheimer's Disease, Key Porter Books, Toronto, Canada, 1998.

4. C. S. Atwood, R. D. Moir, X. Huang et al., “Dramatic aggregation of alzheimer by Cu(II) is induced by conditions representing physiological acidosis,” Journal of Biological Chemistry, vol. 273, no. 21, pp. 12817–12826, 1998. View at Publisher · View at Google Scholar · View at Scopus 

5. A. I. Bush, W. H. Pettingell, G. Multhaup et al., “Rapid induction of Alzheimer Aβ amyloid formation by zinc,” Science, vol. 265, no. 5177, pp. 1464–1467, 1994. View at Scopus 

6. P. A. Adlard, L. Bica, A. R. White, et al., “Metal ionophore treatment restores dendritic spine density and synaptic protein levels in a mouse model of Alzheimer's disease,” PLoS ONE, vol. 6, no. 3, article e17669, 2011.  

7. G. J. Brewer, S. H. Kanzer, E. A. Zimmerman et al., “Subclinical zinc deficiency in Alzheimer's disease and Parkinson's disease,” American Journal of Alzheimer's Disease and other Dementias, vol. 25, no. 7, pp. 572–575, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus 

8. D. Religa, D. Strozyk, R. A. Cherny et al., “Elevated cortical zinc in Alzheimer disease,” Neurology, vol. 67, no. 1, pp. 69–75, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus 


Much more here: 

Posted: Sunday, October 7, 2012 8:10 PM
Joined: 12/20/2011
Posts: 217


Here's another interesting quote from George J. Brewer.  It's important, I think, to note that he thinks the villain isn't "organic copper" (copper in food), but rather the villain is "inorganic copper" (copper in drinking water and in nutritional supplements).  


Here's the quote: 



 We have come up with a hypothesis for a plausible, potentially preventable, cause [of Alzheimer's Disease], namely, ingestion of inorganic copper.

We do not claim this as a sole cause, but rather it, along with a high fat diet, sets the stage for the disease to develop, particularly if other risk factors are present.

What do we mean by inorganic copper?

We differentiate what we call organic copper, which is copper in food, and which is bound up in organic protein molecules, from simple salts of copper not bound to anything.

The latter, inorganic copper, is the kind of copper present in drinking water and in copper supplements present in most available vitamin/mineral supplement pills.

Since there is almost no protein in uncontaminated drinking water, copper leached off copper plumbing pipes will combine with the cations found in drinking water, such as sulfates, carbonates, and phosphates, to form copper sulfate, copper carbonate, and copper phosphate.

Copper added to vitamin/mineral supplement pills is also a simple salt, often copper sulfate.

As I will discuss, I believe inorganic copper, at least in part, is handled differently by the body than organic copper, and ends up in different places...

Much more here: 


Posted: Sunday, October 7, 2012 8:26 PM
Joined: 12/20/2011
Posts: 217


Dietary supplementation with zinc sulphate, sodium selenite and fatty acids in early dementia of Alzheimer's type.

Rhijn, A. G. van; Prior, C. A.; Corrigan, F. M. Journal of Nutritional Medicine 1990 Vol. 1 No. 4 pp. 259-266 ISSN 0955-6664 Record Number 19911431348



The effect in early Alzheimer's disease of dietary supplementation with compounds containing zinc and selenium, and with fatty acids was studied. 36 subjects (≥60 years old) with early dementia of Alzheimer's type were randomly allocated to evening primrose oil/Zn/Se (EPO/Zn/Se) or olive oil treatment and 30 (15 on each treatment) completed the study. Olive oil, originally intended as a placebo, appeared to have some beneficial effect but significant improvements occurred mainly in the EPO/Zn/Se group. This group showed improved performance on the Anomalous Sentences Repetition Test (P>0.005), the Coloured Progressive Matrices (P<0.005), the Graded Naming Test (P<0.005) and the Digit Copying Test (P<0.01). The improvement in the active group may reflect improved mood (P<0.005) and therefore greater alertness, interest and cooperation with the testing.;jsessionid=A71E9027D61BD6AE6F392F7C54A8B4D7 

Posted: Sunday, October 7, 2012 8:36 PM
Joined: 12/20/2011
Posts: 217


Treatment of Alzheimer's disease by zinc compounds

Jean Constantinidis* 

Article first published online: 5 OCT 2004

DOI: 10.1002/ddr.430270102 



At the onset of Alzheimer's disease (AD), specific lesions occur in the hippocampus, i.e., neuropile-capillary amyloid (AM) plaques and neuronal paired-helical filaments (PHF)-neurofibrillary tangles (NFT). The hippocampus is the area of brain with the highest zinc content. Chemical investigations demonstrated that in AD, the cerebral zinc decreases, especially in the hippocampus. The mechanism may be the following: The primary, genetically determined, microvascular AM (asymptomatic) disturbs the blood-brain barrier, and metals (calcium, iron, aluminium, silicon, mercury, etc.( reach the cerebral cortex, where their levels increase and displace the zinc (whose level decreases) in some enzymes which become nonfunctional. The secondary production of PHF-NFT and the neuronal dysfunction responsible of the clinical symptoms of dementia may be related to the functional deficiency of the following zinc-enzymes: (1) those of DNA metabolism giving rise to abnormal DNA and therefore synthesis of abnormal proteins, constituting the NFT; (2) those involved in phosphorylating mechanisms at a post-transcriptional (ribosomal-mitochondrial) level, producing the abnormally phosphorylated tau protein, constituting the PHF; 3) that of glutamate (GLU) catabolism, resulting in a neurotoxic increase of GLU, producing PHF by abnormal phosphorylation of the neurofilaments; 4) those of neuronal detoxification contributing to the neuronal dysfunction. In regard to potential for therapeutic intervention, the timing needed for the AM-induced production of NFT, in the various areas of the brain, has been estimated to be about 14–67 months. During this time it may be possible to influence the AM-induced production of NFT: The chronic administration of neuroleptics enhances it, and the chronic administration of other drugs may reduce it. Such drugs may be zinc compounds, which will give an excess of zinc in the brain, will inhibit the above-mentioned AM induced by zinc deficiency, mechanisms producing the NFT related to the clinical symptoms of dementia, and therefore, may prevent, stop, delay, and even improve them. Preliminary trials with zinc-aspartate give promising results. Research is in progress to consolidate this zinc theory and to find more appropriate zinc compounds for this treatment. 


Lane Simonian
Posted: Sunday, October 7, 2012 9:47 PM
Joined: 12/12/2011
Posts: 4854

Thanks, Onward, for the latest research implicating inorganic copper as playing a role in amyloid plaque formation and Alzheimer's disease, and not zinc, which may instead play a protective role.   


I never thought of copper released into water via copper pipes as a potential risk factor for Alzheimer's disease, but I now see that as a possibility.  If so that makes at least three compounds/elements in water that can potentially trigger Alzheimer's disease: inorganic copper, mercury, and aluminium fluoride. 


I think the primary role of zinc in protecting neurons is by lowering homocysteine levels (and thus peroxynitrite levels), but there may well be other mechanisms involved as well.  Polyunsaturated fatty acids may inhibit the activity of the enzymes that trigger Alzheimer's disease: phospholipase C beta and gamma.  Selenoproteins can scavenge peroxynitrites. 


This may explain the results from the Rhijn study. 

Posted: Tuesday, October 9, 2012 9:26 PM
Joined: 12/20/2011
Posts: 217


Another article of interest:


Alzheimer's memory loss linked to zinc



Published: March. 29, 2012 at 6:06 PM



BOSTON, March 29 (UPI) -- U.S. and Canadian researchers said Alzheimer's disease's memory loss might be due to disruption of micro tubules caused by zinc imbalance.


Senior author Rudolph Tanzi of Harvard said Alzheimer's disease brains have two types of lesions -- beta-amyloid plaques outside neurons, and neurofibrillary tangles within them. The known Alzheimer's disease genes implicate plaques but Alzheimer's disease symptoms correlate more closely with tangles, comprised of "tau" protein, normally adhered to microtubules.


Tanzi said zinc stabilizes many protein complexes, including microtubules, polymers of tubulin, which regulate synapses and play recently revealed key roles in memory encoding in neurons.


Tanzi and colleagues at Boston University, The University of Alberta, The University of Arizona and The Chopra Foundation identified specific zinc-tubulin binding sites promoting side-to-side tubulin interactions.


"It looks like beta-amyloid plaques -- linked to Alzheimer's disease's -- themselves aren't destructive directly but lead to lower zinc levels within neurons. This in turn disrupts microtubules and tau, causing tangles and memory loss," Tanzi said in a statement. "Protecting microtubules and their association with tau may be the best treatment approach in Alzheimer's disease."


The findings published in the journal PLoS One might lead to different therapies. 

Posted: Thursday, October 11, 2012 11:25 AM
Joined: 12/20/2011
Posts: 217


I've been trying to find studies on zinc for cognitive function and/or dementia, to see exactly what kinds of zinc were used, what dosage, and the outcome.  (Admittedly, some of these studies had just a very small number of participants.)  


Adeona's Pharmaceuticals' reaZin zinc tablet, which I think is ZINC CYSTEINE, is said to have failed to help much in a recent trial. 


For dementia, 220 milligrams of ZINC SULFATE (containing 50 milligrams of elemental zinc) has been used by mouth three times daily for 24 weeks.
[Note: I wish I could locate this study to see the outcome.]


Cognitive performance was temporarily improved after 3 months of zinc supplementation (ZINC CHELATE 15 mg) taken twice daily by six subjects with Alzheimer’s disease. Although the initial improvement was not maintained in this small open study, a modest cognitive improvement on psychometric testing was observed at 12 months for the four patients evaluated.


..original study using zinc compounds for the treatment of AD.Ten patients were treated, all of them receiving 50 mg of oral Zinc bis-(DLhydrogenaspartate) TID (three times daily). Improvement of memory, understanding, communication, and social contact were evident in eight patients. In one patient, aged 79, relatively less demented and who received both oral and intravenous ZINC ASPARTATE, the improvement of memory was qualified as ”unbelievable both by the medical staff and the family”. The discontinuation of the treatment decreased and even reversed the improvement, in all patients. However, the small size of the patients’ sample, the design of the study neither blind nor placebo-controlled, makes these results at least concerning. Even though those conclusions have to be taken very cautiously, it seems surprising that nobody tried to replicate them in larger samples and using proper study design.

[The study: 

Constantinidis J. Treatment of Alzheimer's disease by zinc compounds.
Drug Dev Res 1992; 27(1): 1-14.]



Posted: Friday, October 12, 2012 6:55 PM
Joined: 12/20/2011
Posts: 217



October 1, 2012 05:21 PM

A new study has outlined for the first time a biological mechanism by which zinc deficiency can develop with age, leading to a decline of the immune system and increased inflammation associated with many health problems, including cancer, heart disease, autoimmune disease and diabetes.

The research was done by scientists in the Linus Pauling Institute at Oregon State University and the OSU College of Public Health and Human Sciences. It suggests that it's especially important for elderly people to get adequate dietary intake of zinc, since they may need more of it at this life stage when their ability to absorb it is declining.


About 40 percent of elderly Americans and as many as two billion people around the world have diets that are deficient in this important, but often underappreciated micronutrient, experts say.


The study was published in the Journal of Nutritional Biochemistry, based on findings with laboratory animals. It found that zinc transporters were significantly dysregulated in old animals. They showed signs of zinc deficiency and had an enhanced inflammatory response even though their diet supposedly contained adequate amounts of zinc.


When the animals were given about 10 times their dietary requirement for zinc, the biomarkers of inflammation were restored to those of young animals.


"The elderly are the fastest growing population in the U.S. and are highly vulnerable to zinc deficiency," said Emily Ho, an LPI principal investigator. "They don't consume enough of this nutrient and don't absorb it very well."


"We've previously shown in both animal and human studies that zinc deficiency can cause DNA damage, and this new work shows how it can help lead to systemic inflammation," Ho said.


"Some inflammation is normal, a part of immune defense, wound healing and other functions," she said. "But in excess, it's been associated with almost every degenerative disease you can think of, including cancer and heart disease. It appears to be a significant factor in the diseases that most people die from."


As a result of this and what is now know about zinc absorption in the elderly, Ho said that she would recommend all senior citizens take a dietary supplement that includes the full RDA for zinc, which is 11 milligrams a day for men and 8 milligrams for women. Zinc can be obtained in the diet from seafood and meats, but it's more difficult to absorb from grains and vegetables – a particular concern for vegetarians.


"We found that the mechanisms to transport zinc are disrupted by age-related epigenetic changes," said Carmen Wong, an OSU research associate and co-author of this study. "This can cause an increase in DNA methylation and histone modifications that are related to disease processes, especially cancer. Immune system cells are also particularly vulnerable to zinc deficiency."


Research at OSU and elsewhere has shown that zinc is essential to protect against oxidative stress and help repair DNA damage. In zinc deficiency, the risk of which has been shown to increase with age, the body's ability to repair genetic damage may be decreasing even as the amount of damage is going up.


Medical tests to determine zinc deficiency are rarely done, scientists say, and are not particularly accurate even if they are done. The best approach is to assure adequate intake of the nutrient through diet or supplements, they said, especially in the elderly


Even though elderly people have less success in absorbing zinc, the official RDA for them is the same as in younger adults. That issue should be examined more closely, Ho said.


Levels of zinc intake above 40 milligrams per day should be avoided, researchers said, because at very high levels they can interfere with absorption of other necessary nutrients, including iron and copper. 

Posted: Saturday, October 13, 2012 5:45 PM
Joined: 12/20/2011
Posts: 217



"... Preliminary research had suggested that people with Alzheimer's disease should avoid zinc supplements. More recently, preliminary evidence in four patients actually showed improved mental function with zinc supplementation.15 In a convincing review of zinc/Alzheimer’s disease research, perhaps the most respected zinc researcher in the world concluded that zinc does not cause or exacerbate Alzheimer’s disease symptoms.16..."  



15. Potocnik FCV, van Rensburg SJ, Park C, et al. Zinc and platelet membrane microviscosity in Alzheimer’s disease. S Afr Med J 1997;87:1116–9.


16. Prasad AS. Zinc in human health: an update. J Trace Elem Exp Med 1998;11:63–87. 




Zinc and platelet membrane microviscosity in Alzheimer's disease. The in vivo effect of zinc on platelet membranes and cognition

Potocnik, F. C. V. Van Rensburg, S. J. Park, C. Taljaard, J. J. F. Emsley, R. A. 


Objectives. To investigate the effects of oral zinc supplementation on: (i) plasma zinc concentrations; (ii) platelet membrane microviscosity in vivo; and (iii) cognitive function of Alzheimer's disease (AD) patients. Design. An open-labelled pilot study. Setting. University of Stellenbosch Medical School and Stikland Hospital. Subjects. Six volunteer AD patients. Outcome measures. Plasma zinc levels, platelet membrane microviscosity and cognition (MMSE) and ADAS-cog tests). Results. Oral zinc supplementation (30 mg/day) did not increase plasma zinc levels significantly, but significantly increased platelet membrane microviscosity (P = 0.02; 6 patients). Four patients, who underwent 12 months of evaluation, showed modest cognitive improvement on psychometric testing (Mini-Mental State Examination and the cognitive portion of the Alzheimer's Disease Assessment scale scores). Conclusions. While earlier literature promoted the use of zinc in AD patients, a recent study has contradicted this and implicated zinc in the aetiology of Alzheimer's disease. On the basis of the above results, it may be premature to single out zinc as a causal agent in AD. 




Text file of the above study is available at
It appears to be a scanned document with many typos.  I tried to decipher it below:

Recent years have led to the discovery of several genetic
components implicated in the aetiology of Alzheimer's
disease (AD).' Environmental factors, however, are believed
to accelerate disease expression in genetically susceptible
individuals, as is evidenced by the fact that in monozygotic
twins, age of onset of AD may differ by as much as 15
years, or that the twins may even be discordant for the

This contrasts with Huntington's disease, in which
no discordancy has been reported. The discovery of
environmental factors responsible for AD in vulnerable
individuals and protection against them could conceivably
alter the date of onset, severity and course of the disease.

A delay in the onset of AD by only 5 years would halve the
prevalence of the illness, resulting in enormous cost-savings
and preventing much human misery.

Atthough AD is seen as a disease of the brain, there is
mounting evidence that peripheral cells are also affected.
In 1987 Zubenko et al. discovered reduced platelet
membrane microviscosity (reciprocal of membrane fluidity) in
55% of AD patients, as well as 8% of healthy control

Because this abnormality in platelet membrane
microviscosity occurred in only half of all AD patients, it could
not be used as a diagnostic marker for AD. The observation
that a small proportion of healthy control subjects as well as
some healthy first degree relatives had lowered platelet
membranemicroviscosity has led to speculation about the
susceptibility of these individuals to AD in later life. A long
tenn prospective study, however, would be required to
establish whether this is indeed the case.

Other authors have confirmed the presence of decreased
platelet membrane microviscosity in AD patients.
It has recently come to light that free radical-derived lipid
peroxidation decreases platelet membrane microviscosity,
and that high levels of ascorbic acid eliminate the
membrane damage in the in vitro system.

Zinc also decreases lipid peroxidation in vitro. Jeandel et al. found
that the blood concentrations of several free-radical
scavengers that protect against free radical damage,
including ascorbate and zinc, were significantly lower in AD
patients than in control subjects.

Metal ions alter platelet membrane microviscosity by
binding to charged headgroups of membrane

Van Rensburg et al. demonstrated that
aluminium ions decreased while zinc ions increased the
microviscosity of platelet membranes in vitro.
A role for zinc in dementia is suggested by the fact that
reduced levels of zinc are found in both plasma and brain
tissue of AD patients, especially in the hippocampus.

The highest concentration of zinc in the brain is found in the
hippocampal mossy fibres, localised in excitatory boutons,
where zinc is co-released with glutamate during neuronal
activity in the form of dense synaptic vesicles.

Westbrook and Mayer suggested that zinc may regulate both excitatory
and inhibitory synaptic transmission in the hippocampus and
that zinc may therefore play an important role in long-term
potentiation,  in the processing of memory formation.

In 1992 a hypothesis was put forward that zinc deficiency
in the hippocampus may contribute to the pathogenesis of
neurofibrillary tangles and that this may be prevented by
treatment with zinc compounds.

Recently, Bush et al. contested this line of thinking by postulating that zinc
actually contributed to AD by precipitating amyloid.This
experiment essentially consisted of adding zinc to a-amyloid
in a test tube and finding the latter aggregated.

While Mantyh et al. showed that aluminium and iron, as
well as zinc, in high concentrations were capable of
aggregating a-amyloid, Bush et al. also reported a negative
effect of zinc on the cognition of a small sample (the number
of patients and the dosage of zinc administered were not
published) of AD patients within a few days of starting

These findings did not concur with the
results of our own work in progress at the time.

An open-labelled study was undertaken to investigate the
in vivo effects of oral zinc supplementation on: (I) plasma zinc
concentration; (iI) platelet membrane microviscosity; and (iil)
cognitive function of AD patients over a l-year period.

Patients and methods
Six patients (4 men and 2 women; mean age 63.6 years,
range 51 - 79) were diagnosed with AD according to the
definition given by the National Institute of Neurological and
Communicative Disorders and Stroke - Alzheimer's Disease
and Related Disorders Association (NINCDS-ADRDA) work
group and the criteria in the DSM-II/-R,20 as described

The mean Mini-Mental State Examination
(MMSE score for the patients before supplementation was
16 out of 30 (range 12 - 21). The study was approved by the
Ethics Committee of the University of Stellenbosch.

The 6 AD patients were given oral zinc in the form of ZINC
(15 mg twice daily).

Plasma zinc levels and platelet membrane microviscosity were measured
before, during and after the supplementation period. The
patients acted as their own controls.

Plasma zinc levels were determined with a Varian Techtron
Model 1200 atomic absorption spectrophotometer. Platelet
membranes were isolated, and membrane microviscosity
(reciprocal of membrane flUidity) was determined by the
method of Zubenko et al.

The cognitive functioning of 4 AD patients (2 men and 2
women; mean age 67.7 years, range 63 - 72; mean MMSE
18, range 14 - 21) was monitored over a l-year period by
the quarterly administration of a psychometric test battery
which included the MMSE and the cognitive portion of the
Alzheimer's Disease Assessment Scale (ADAS-eog). These
patients were receiving oral zinc chelated with methionine
(15 mg twice daily).


In spite of oral zinc supplementation, the resulting plasma
zinc levels were variable, and even decreased in 2 instances
(Table I). Normal plasma zinc values range between 14 and

In all 6 patients, the platelet membrane microviscosity
values increased to reach similar values within 1 - 3 months
(Patients A - F; Fig. 1). For the group, the increase was
statistically significant (P = 0.02; Wilcoxon rank test).
Increased platelet membrane microviscosity values were
sustained, provided zinc supplementation continued (results
not shown).

Following the initiation of zinc supplementation, all 4
patients showed a modest temporary peak in psychometric
performance at the 3-month mark, relative to their baseline
test scores on the same battery.

This cognitive improvement
coincided with the caregivers' reports of improved day-to
day functioning and was also reflected in the MMSE scores

(Fig. 2). For the MMSE, the highest score is 30...

... For the MMSE, the expected decline is
2.4 • 3 points per year.

... The MMSE decline for the 4 AD patients
after 1 year of zinc supplementation was less than expected

For the ADAS-eog, the perfect score is 0, and in AD an
increase of some 7 - 9 points per year is to be expected.
Again, the decline in cognition of the 4 AD patients after
1 year of zinc supplementation was less than expected

... At the described dosages of zinc
supplementation, all our patients were cognitively better off
after 1 year than if they had not taken zinc.

These results
are in agreement with those obtained by Van Rhijn et al.,
who showed that 15 AD patients receiving dietary
supplementation of zinc sulphate, sodium selenite and fatty
acids over a 20-week period showed significantly improved
performance on psychometric testing.


The negative effect
observed by Bush et al. in his AD patients within a few days
of zinc supplementation (dosage not pUblished) may have
been due to aluminium, rather than zinc. As a general
principle, an addition of one metal to the body leads to the
redistribution of other metals. linc has been shown to cause
the release of aluminium from membranes and, as
demonstrated previously, aluminium in this free form would
have negative effects on several systems in the body,
causing nuclear damage and alteration of neurotransmitter
and enzyme functions.

Higher levels of zinc would compound this effect.
Furthermore, the very high levels of zinc found in the
hippocampus are enclosed in protective membranous
vesicles. In vitro experiments would not account for this.
In 2 of the 6 patients receiving zinc supplementation, an
increase in libido occurred, necessitating the prescription of
cyproterone acetate. A rise in libido following zinc
supplementation has previously been noted in the


Zinc supplementation unexpectedly did not result in higher
plasma zinc levels in all patients. The variable plasma zinc
levels found may have reflected either a defect in the
absorption of zinc (unlikely, see below) or immediate
redistribution of absorbed zinc into body stores.

The 6 AD patients who received oral zinc supplementation
displayed a steady increase in platelet membrane
microviscosity. This suggests that zinc plays an important
role in maintaining the patency of the microviscosity of
membranes in the body. This role could bestructural, in
that zinc may bind to the charged headgroups of
phospholipids in membranes, or produce an atteration of
the phospholipid composition of the membranes. Driscoll
andBettge found that dietary zinc deficiency in rats
caused a change in erythrocyte phospholipid composition.

Zinc may also protect platelet membranes from decreased
membrane microviscosity caused by lipid peroxidation,8
through the inhibition of free radical reactions.

The fact that oral zinc supplementation had a positive
effect on platelet membrane microviscosity in the presence
of variable plasma zinc levels, indicates that the latter does
not reflect the zinc concentration present in these

Though preliminary, the results counter the claims made
by Bush et al. that zinc adversely affects... cognition...


Zinc supplementation corrected the membrane
microviscosity of platelets in a sample of 6 AD patients.
A further ongoing study of 4 patients showed that zinc
supplementation resulted in a modest temporary
improvement in the cognition of all of these patients, as
observed on psychometric testing. This is at variance with
Bush et al.'s report of rapid cognitive deterioration in AD
patients receiving zinc supplementation. The latter effect
may have been dose-related, thus altering the distribution of
and upsetting the balance of other metals in the body, with
negative consequences. We feel that it may be premature to
single out zinc as a causal agent in AD.




Lane Simonian
Posted: Saturday, October 13, 2012 6:32 PM
Joined: 12/12/2011
Posts: 4854

A few thoughts--some of which may be wrong.  Even if zinc does not play a role in the aggregation of amyloid plaques (which looks more and more likely), if it is absorbed by the plaques anyway then zinc supplementation may not work while the plaques are aggregating.  The enzyme that triggers the aggregation of plaques---phospholipase C--may trigger the export of zinc (further leading to zinc deficiency) and this extracellular zinc may in turn increase phospholipase C activity.  If this is the case, zinc supplementation during the early stages of Alzheimer's disease may be a problem. (the authors of this article argue that at least in certain cells zinc does not increase phospholipase C activity). (the role of phospholipase C in the formation of amyloid plaques). 


Once phospholipase C activity slows down and thus the aggregation of plaques slows down, zinc supplementation may be helpful--because zinc inhibits the further formation of peroxynitrites (the toxin that likely causes Alzheimer's disease).  It does so by lowering homocysteine levels and by increasing superoxide dismutase activity--the zinc-copper driven enzyme that converts superoxide anions into hydrogen peroxide (superoxide anions combine with inducible nitric oxide to form peroxynitrites). 


I hate it when studies seem to produce contradictory results.  This is just one possible explanation around the apparent contradiction--zinc may be harmful or neutral early on and helpful later on. 

Posted: Sunday, October 14, 2012 11:23 AM
Joined: 12/20/2011
Posts: 217

Hi, Lane.  Thanks as always for the input.  Ah, if only we had definitive answers for all these things... Obviously much more research is needed.


The following is purely anecdotal, I know, but I still found it interesting in light of the sometimes encouraging results in studies cited in earlier posts.  It's very intriguing to think that zinc supplementation just might help significantly in some cases, even though not in all cases:


Lane Simonian
Posted: Sunday, October 14, 2012 3:30 PM
Joined: 12/12/2011
Posts: 4854

Thanks, Onward, for your research on zinc and all of your research.  I always take anecdotal report seriously.  Where improvements are reported there is almost always something behind it (and even more so in cases like this where there is additional evidence).  I do indeed hope that future research will indicate who may be best helped by zinc supplementation (and in what form) or at what stages in the disease. 
Posted: Friday, October 19, 2012 8:39 PM
Joined: 12/20/2011
Posts: 217


Came across this article advocating zinc therapy:


International Journal of Alzheimer’s Disease
Volume 2011, Article ID 492686, 6 pages



Paradigm Shift in Treatment of Alzheimer's Disease:

Zinc Therapy Now a Conscientious Choice for Care of Individual Patients


Tjaard U. Hoogenraad 

Department of Neurology, University Medical Centre, Utrecht, 3941 VD 20 Utrecht, The Netherlands



Breakthrough in treatment of Alzheimer’s disease with a shift from irrational dangerous chelation therapy to rational safe evidence based oral zinc therapy.

Evidence based medicine: After synthesizing the best available clinical evidence I conclude that oral zinc therapy is a conscientious choice for treatment of free copper toxicosis in individual patients with Alzheimer’s disease.

Hypothesis 1: Age related free copper toxicosis is a causal factor in pathogenesis of Alzheimer’s disease.

There are 2 neurodegenerative diseases with abnormalities in copper metabolism:

(a) the juvenile form with degeneration in the basal ganglia (Wilson’s disease)


and (b) the age related form with cortical neurodegeneration (Alzheimer’s disease).

Initially the hypothesis has been that neurodegeneration was caused by accumulation of copper in the brain but later experiences with treatment of Wilson’s disease led to the conviction that free plasma copper is the toxic form of copper: it catalyzes amyloid formation thereby generating oxidative stress, free radicals and degeneration of cortical neurons.

Hypothesis 2: Oral zinc therapy is an effective and safe treatment of free copper toxicosis in Alzheimer’s disease.  Proposed dosage: 50mg elementary zinc/day.

Warning: Chelation therapy is irrational and dangerous in treatment of copper toxicosis in Alzheimer’s disease...

See the full paper here:


And here's a recent and very technical article that may be of interest:


Unraveling the role of zinc in memory





PNASvol. 108 no. 8 3103-3104

See the article here




Lane Simonian
Posted: Friday, October 19, 2012 11:08 PM
Joined: 12/12/2011
Posts: 4854

The first study may explain why efforts to pull out both zinc and copper from amyloid plaques have failed to produce any improvements in memory for those with Alzheimer's disease.  It would be interesting to see if compounds that just bound to zinc (and removed them from the plaques) would result in improved memory in people with Alzheimer's disease.  Still not sure if zinc supplementation would work at all stages of the disease or only after the production of amyloid plaques significantly slowed down.
Posted: Saturday, October 20, 2012 9:07 AM
Joined: 12/20/2011
Posts: 217

 Thanks, Lane.  Obviously I don't know either.  Interesting, though, that the Van Rhijn study was done specifically on early-stage Alzheimer's patients.  Of course that study involved more than just zinc supplementation though.


Dietary supplementation with zinc sulphate, sodium selenite and fatty acids in early dementia of Alzheimer's type.;jsessionid=A71E9027D61BD6AE6F392F7C54A8B4D7

Lane Simonian
Posted: Saturday, October 20, 2012 10:23 AM
Joined: 12/12/2011
Posts: 4854

The article that you cited above, Onward, suggests that zinc can help memory by activating ERK.  This study suggests the same for sodium selenite. 


The following study suggests that ERK activation may be detrimental as the disease progresses. 


On the other hand, zinc may lower homocysteine levels which would be helpful as the disease progresses.  Long-term studies are needed to answer the question of whether zinc supplementation would be useful or not at different stages of the disease. 

Posted: Saturday, October 20, 2012 11:52 AM
Joined: 12/20/2011
Posts: 217

Lane Simonian wrote:

The article that you cited above, Onward, suggests that zinc can help memory by activating ERK.  This study suggests the same for sodium selenite. 


The following study suggests that ERK activation may be detrimental as the disease progresses. 


On the other hand, zinc may lower homocysteine levels which would be helpful as the disease progresses.  Long-term studies are needed to answer the question of whether zinc supplementation would be useful or not at different stages of the disease. 

Thanks for finding that, Lane.  Interesting that zinc can activate ERK.  Flavonoids, which have been found to reduce rates of cognitive decline, activate ERK.  Polyphenols also activate ERK.

So I'm guessing that flavonoids and polyphenols (and zinc?) are performing very complex roles that may possibly offset the possible negatives of ERK activation?  I don't know.


Dietary Intakes of Berries and Flavonoids in Relation to Cognitive Decline


"Higher intake of flavonoids, particularly from berries, appears to reduce rates of cognitive decline in older adults...


"... flavonoid-rich foods can activate extracellular receptor kinase [ERK] and protein kinase B/Akt pathways, which are thought to enhance memory and




And about polyphenols activating ERK:


Polyphenols and human health: prevention of disease and mechanisms of action.  


 "Rather than exerting direct antioxidant effects, the mechanisms by which polyphenols express these beneficial properties appear to involve their interaction with cellular signaling pathways and related machinery that mediate cell function under both normal and pathological conditions. We illustrate that their interactions with two such pathways, the MAP kinase (ERK, JNK, p38 )  and PI3 kinase/Akt signaling cascades, allow them to impact upon normal and abnormal cell function, thus influencing the cellular processes involved in the initiation and progression of cancer, CVD and neurodegeneration. For example, their ability to activate ERK in neurons leads to a promotion of neuronal survival and cognitive enhancements, both of which influence the progression of Alzheimer's disease, whilst ERK activation by polyphenols in vascular endothelial cells influences nitric oxide production, blood pressure and ultimately CVD risk." Source (PubMed) 

Your understanding of science is obviously light years ahead of mine, Lane.  I'm mostly limited to just googling stuff and quoting.  So admittedly I can't grasp all these technical details like you and some others on this board are able to do (and we who can't grasp it appreciate those of you who can).







Lane Simonian
Posted: Saturday, October 20, 2012 7:18 PM
Joined: 12/12/2011
Posts: 4854

Yes, it is aggravatingly complicated at times.  I knew some biology before I began studying this disease, but knew nothing about the pathways that may lead to Alzheimer's disease.  You are right there with me Onward, just reading study after study trying to make what sense we can out of them. 


The critical substrate in Alzheimer's disease  is called phosphatidyinositol 4,5 biphosphate.  When it is acted upon by phosphatidylinositol 3 kinase it leads to Akt/Protein kinase B.  This pathway largely helps to protect against Alzheimer's disease (presenilin gene mutations, the APOE4 gene, and bisphosphonate osteoporosis drugs inhibit this pathway to varying degrees). When phosphatidylinositol 3,4 biphosphate is acted upon by phospholipase C (gamma or beta) it leads to intracellular calcium release and Protein kinase C which is the trigger for amyloid plaques, peroxynitrites, and Alzheimer's disease. 



Zinc activates the PI3 kinase/Akt, perhaps through presenilins or perhaps through the activation of the insulin-like growth factor receptor. 



The big unanswered question, though, is whether, zinc activates phopholipase C. 


Flavonoids inhibit phospholipase C and thus protein kinase C, and through different means can either inhibit or activate the PI3 kinase/Akt. 


As the article you posted suggests, it is not only the fact that flavonoids are antioxidants, they inhibit one of the key enzymes that lead to Alzheimer's disease (phospholipase C gamma).  And omega 3-fatty acids inhibit the activity of both forms of phospholipase C.  The combination of phenolic compounds (including flavonoids) and Omega 3-fatty acids provide a good combination to delay the onset of Alzheimer's disease. 


Lane Simonian
Posted: Saturday, October 20, 2012 7:51 PM
Joined: 12/12/2011
Posts: 4854

I made it too complicated.  The following pathway largely protects memory: PI3 kinase/akt/ERK.  The following pathway leads to Alzheimer's disease phospholipase C/Protein kinase C/ERK.  If zinc stimulates the first pathway more than the second it may be beneficial.  As the disease progresses, both pathways are cut off and zinc may help by lowering homocysteine levels.
Lane Simonian
Posted: Sunday, October 21, 2012 9:18 AM
Joined: 12/12/2011
Posts: 4854

It appears that zinc in the hippocampus does increase intracellular calcium release via a g-protein coupled receptor (which activates phospholipase C beta) so this might account for the negative studies regarding zinc and memory in Alzheimer's disease. 


Zinc also appears to help activate the phosphatidylinositol 3 kinase/Akt which would explain the positive studies in regards to zinc and memory in Alzheimer's disease. 


More definitive studies are needed.  Zinc supplementation once the above pathways are cut off should have a positive influence. 

Posted: Wednesday, October 24, 2012 12:16 PM
Joined: 4/24/2012
Posts: 484


Lane and onward,

Thank you so much for all the good information and studies you have posted. I have reviewed much of the Copper and Zinc-related research and would like to get your thoughts on the following observation.

Concerning G. Brewer's excess inorganic Copper hypothesis (, he states: "Alzheimer's disease (AD) has become an epidemic in developed, but not undeveloped, countries and that the epidemic is a new disease phenomenon, beginning in the early 1900s and exploding in the last 50 years."

Rapamycin has been shown to inhibit the mTOR pathway which upregulates Autophagy and has been shown to work in mouse models ( I believe the dysregulation of Autophagy is a key factor in AD pathogenisis, and it's interesting that fasting is also known to inhibit the mTOR pathway. Would it not follow Brewer's basic philosophy that fasting is virtually nonexistant in the developed world but common in the undeveloped world. Even the poor don't miss meals in this country and the constant intake of nutrients is part of the signaling pathway for the upregulation of mTOR which in turn inhibits Autophagy.

I would like to draw some connections and find some commonalities with potential environmental causes that are supported by detailed biological research. This may lead us to a workable strategy that involves a combination of readily accessible teatments: Zinc supplimentation, fasting, diet, or even Rapamycin, Bexatotene, Leukine, IgIV, etc.

Posted: Wednesday, October 24, 2012 3:02 PM
Joined: 12/20/2011
Posts: 217


Serenoa, I'm sorry that I don't understand the science well enough to comment.  But maybe others here, such as Lane, can shed more light.

Thanks for your post.  I'll be interested to hear more, especially about potential treatments, as you pursue this. 

Posted: Wednesday, October 24, 2012 8:37 PM
Joined: 4/24/2012
Posts: 484

All your posts have been very informative onward. The science is over my head too, but I have learned a lot over the past two years. It seems to me that us novices are going to have to put the clues together ourselves and come up with solutions. There is a huge gap between the researchers and the doctors.


My mother tried Leukine a year and a half ago, six weeks of treatments. There seemed to be improvement in her condition, but it is expensive and others haven't seen the same results. So I continue to search for something better.

Posted: Wednesday, October 24, 2012 9:12 PM
Joined: 12/20/2011
Posts: 217



Serenoa, thanks.  I appreciate your tenacity and optimism and look forward to more posts from you.  It helps as we share what we find and what we think.  I know I've learned a lot through others who post here.  Am curious to know if you've seen positive results from anything else, other than the Leukine, that you've tried. 

Lane Simonian
Posted: Wednesday, October 24, 2012 9:40 PM
Joined: 12/12/2011
Posts: 4854

Welcome, Serenoa.  I agree that many people on this board are helping to provide keen insights into the potential treatment of Alzheimer's disease.   


I believe the reason for the low levels of Alzheimer's disease in many developing countries can largely be explained by diets which feature spices, herbs, teas, vegetables, and fruits and a reduced exposure to industrial toxins (such as copper, aluminium fluoride, and mercury).  This may also help to partially explain why in developing countries the rates are lower in rural areas than in urban areas.  In developed countries, places where a Mediterranean diet is adhered too or where there is high consumption of fish, green tea, rice bran, etc. (such as Japan) also have lower incidences of Alzheimer's disease. 


The principal action of rapamcyin in terms of potentially helping against Alzheimer's dsiease is likely through the inhibition of Protein kinase C, which leads to the formation of peroxynitrites--a principal oxidant in Alzheimer's disease.  Bexarotene may also inhibit the formation of peroxynitrites.  Leukine and intravenous immunoglobulin are designed to lower plaque levels which should also lessen peroxynitrite formation. 


Phenolic compounds in various fruits, vegetables, spices, teas, and essential oils and polyunsaturated fats such as fish oil also inhibit the formation of peroxnitrites. Potentially, they may help delay the onset of Alzheimer's disease. 



Methoxyphenols are likely the best compounds for treating the disease.  They are effective peroxynitrites scavengers and partially repair the damage that peroxynitrites do to critical transport systems, enzymes, and receptors in the brain.  Eugenol in rosemary essential oil via aromatherapy and coumaric acid, ferulic acid, syringic acid, and vanillic acid in heat-processed ginseng are examples of methoxyphenols that have led to significant improvements in cognitive function in Alzheimer's patients in small-scale clinical trials. 


Inhibit the formation of peroxynitrites and you can delay the onset of Alzheimer's disease; scavenge and partially reverse the damage done by peroxynitrites and you can treat Alzheimer's disease. 





Posted: Sunday, November 11, 2012 3:33 AM
Joined: 4/24/2012
Posts: 484

You guys are making it so much easier to find and compare the relavant research for these various potential causes of AD. Thank you. I am getting better at using this discussion board format and will make sure in the future to review all the previous posts in the string and keep my own posts relevant to the main topic.