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2012 study: Zinc supplementation improves cognition in Alzheimer's Disease
Found this interesting: Copper excess, zinc deficiency, and cognition loss in Alzheimer's disease
George J. Brewer
Article first published online: 22 MAR 2012
Copyright © 2012 International Union of Biochemistry and Molecular Biology, Inc
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 reviewhttp://www.ncbi.nlm.nih.gov/pubmed/22583839
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 Diseasehttp://www.hindawi.com/journals/ijad/2011/537528/Also see:The Risks of Copper Toxicity Contributing to Cognitive Decline in the Aging
Population and to Alzheimer's Diseasehttp://www.jacn.org/content/28/3/238.full
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? http://www.livestrong.com/article/390781-does-zinc-help-the-brain-with-memory/
Adeona's Pharmaceuticals' reaZin zinc tablet, which I think is zinc cysteine, failed to help much in a recent trial.http://www.thestreet.com/print/story/11083931.html 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.
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.
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.
Lane and Tom(ek), I appreciate your input.
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:
George J. Brewer
... One of the hallmarks of AD pathology in the brain is extracellular amyloid plaques . 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 . It is already known, based on serum zinc levels, that AD patients are zinc deficient , 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 . 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: http://www.hindawi.com/journals/ijad/2011/537528/
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: http://www.hindawi.com/journals/ijad/2011/537528/
Dietary supplementation with zinc sulphate, sodium selenite and fatty acids in early dementia of Alzheimer's type.
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.
Article first published online: 5 OCT 2004
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.
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.
Another article of interest:
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
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.http://www.thestreet.com/print/story/11083931.html ________________________________________________For dementia, 220 milligrams of ZINC SULFATE (containing 50 milligrams of elemental zinc) has been used by mouth three times daily for 24 weeks. http://www.mayoclinic.com/health/zinc/NS_patient-zinc/DSECTION=dosing[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. http://medicinalplants.us/zinc-other-uses_________________________________________________
and older adults: the ZENITH study(2006), 96, 752–760 DOI: 10.1079/BJN20061911
..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.]
October 1, 2012 05:21 PMA 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
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. http://www.biologynews.net/archives/2012/10/01/zinc_deficiency_mechanism_linked_to_aging_multiple_diseases.html
"... 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
16. Prasad AS. Zinc in human health: an update. J Trace
Elem Exp Med 1998;11:63–87.
Text file of the above study is available athttp://scholar.sun.ac.za/bitstream/handle/10019.1/7217/potocnik_zinc_1997.pdf.txt?sequence=2It appears to be a scanned document with many typos. I tried to decipher it below:Recent years have led to the discovery of several geneticcomponents implicated in the aetiology of Alzheimer'sdisease (AD).' Environmental factors, however, are believedto accelerate disease expression in genetically susceptibleindividuals, as is evidenced by the fact that in monozygotictwins, age of onset of AD may differ by as much as 15years, or that the twins may even be discordant for thedisease.This contrasts with Huntington's disease, in whichno discordancy has been reported. The discovery ofenvironmental factors responsible for AD in vulnerableindividuals and protection against them could conceivablyalter the date of onset, severity and course of the disease.A delay in the onset of AD by only 5 years would halve theprevalence of the illness, resulting in enormous cost-savingsand preventing much human misery.Atthough AD is seen as a disease of the brain, there ismounting evidence that peripheral cells are also affected.In 1987 Zubenko et al. discovered reduced plateletmembrane microviscosity (reciprocal of membrane fluidity) in55% of AD patients, as well as 8% of healthy controlsubjects.Because this abnormality in platelet membranemicroviscosity occurred in only half of all AD patients, it couldnot be used as a diagnostic marker for AD. The observationthat a small proportion of healthy control subjects as well assome healthy first degree relatives had lowered plateletmembranemicroviscosity has led to speculation about thesusceptibility of these individuals to AD in later life. A long tenn prospective study, however, would be required toestablish 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 lipidperoxidation decreases platelet membrane microviscosity,and that high levels of ascorbic acid eliminate themembrane damage in the in vitro system.Zinc also decreases lipid peroxidation in vitro. Jeandel et al. foundthat the blood concentrations of several free-radicalscavengers that protect against free radical damage,including ascorbate and zinc, were significantly lower in ADpatients than in control subjects.Metal ions alter platelet membrane microviscosity bybinding to charged headgroups of membranephospholipids.Van Rensburg et al. demonstrated thataluminium ions decreased while zinc ions increased themicroviscosity of platelet membranes in vitro.A role for zinc in dementia is suggested by the fact thatreduced levels of zinc are found in both plasma and braintissue of AD patients, especially in the hippocampus.The highest concentration of zinc in the brain is found in thehippocampal mossy fibres, localised in excitatory boutons,where zinc is co-released with glutamate during neuronalactivity in the form of dense synaptic vesicles.Westbrook and Mayer suggested that zinc may regulate both excitatoryand inhibitory synaptic transmission in the hippocampus andthat zinc may therefore play an important role in long-termpotentiation, in the processing of memory formation.In 1992 a hypothesis was put forward that zinc deficiencyin the hippocampus may contribute to the pathogenesis ofneurofibrillary tangles and that this may be prevented bytreatment with zinc compounds.Recently, Bush et al. contested this line of thinking by postulating that zincactually contributed to AD by precipitating amyloid.Thisexperiment essentially consisted of adding zinc to a-amyloidin a test tube and finding the latter aggregated.While Mantyh et al. showed that aluminium and iron, aswell as zinc, in high concentrations were capable ofaggregating a-amyloid, Bush et al. also reported a negativeeffect of zinc on the cognition of a small sample (the numberof patients and the dosage of zinc administered were notpublished) of AD patients within a few days of startingsupplementation.'These findings did not concur with theresults of our own work in progress at the time.An open-labelled study was undertaken to investigate thein vivo effects of oral zinc supplementation on: (I) plasma zincconcentration; (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 thedefinition given by the National Institute of Neurological andCommunicative Disorders and Stroke - Alzheimer's Diseaseand Related Disorders Association (NINCDS-ADRDA) workgroup and the criteria in the DSM-II/-R,20 as describedpreviously.The mean Mini-Mental State Examination(MMSE score for the patients before supplementation was16 out of 30 (range 12 - 21). The study was approved by theEthics Committee of the University of Stellenbosch.The 6 AD patients were given oral zinc in the form of ZINCCHELATED WITH METHIONINE (15 mg twice daily). Plasma zinc levels and platelet membrane microviscosity were measuredbefore, during and after the supplementation period. Thepatients acted as their own controls.Plasma zinc levels were determined with a Varian TechtronModel 1200 atomic absorption spectrophotometer. Plateletmembranes were isolated, and membrane microviscosity(reciprocal of membrane flUidity) was determined by themethod of Zubenko et al.The cognitive functioning of 4 AD patients (2 men and 2women; mean age 67.7 years, range 63 - 72; mean MMSE18, range 14 - 21) was monitored over a l-year period bythe quarterly administration of a psychometric test batterywhich included the MMSE and the cognitive portion of theAlzheimer's Disease Assessment Scale (ADAS-eog). Thesepatients were receiving oral zinc chelated with methionine(15 mg twice daily).ResultsIn spite of oral zinc supplementation, the resulting plasmazinc levels were variable, and even decreased in 2 instances(Table I). Normal plasma zinc values range between 14 and34...
In all 6 patients, the platelet membrane microviscosityvalues increased to reach similar values within 1 - 3 months(Patients A - F; Fig. 1). For the group, the increase wasstatistically significant (P = 0.02; Wilcoxon rank test).Increased platelet membrane microviscosity values weresustained, provided zinc supplementation continued (resultsnot shown).Following the initiation of zinc supplementation, all 4patients showed a modest temporary peak in psychometricperformance at the 3-month mark, relative to their baselinetest scores on the same battery.This cognitive improvementcoincided 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 is2.4 • 3 points per year.
... The MMSE decline for the 4 AD patientsafter 1 year of zinc supplementation was less than expectedFor the ADAS-eog, the perfect score is 0, and in AD anincrease of some 7 - 9 points per year is to be expected.Again, the decline in cognition of the 4 AD patients after1 year of zinc supplementation was less than expected
... At the described dosages of zincsupplementation, all our patients were cognitively better offafter 1 year than if they had not taken zinc.These resultsare in agreement with those obtained by Van Rhijn et al.,who showed that 15 AD patients receiving dietarysupplementation of zinc sulphate, sodium selenite and fattyacids over a 20-week period showed significantly improvedperformance on psychometric testing.
The negative effectobserved by Bush et al. in his AD patients within a few daysof zinc supplementation (dosage not pUblished) may havebeen due to aluminium, rather than zinc. As a generalprinciple, an addition of one metal to the body leads to theredistribution of other metals. linc has been shown to causethe release of aluminium from membranes and, asdemonstrated previously, aluminium in this free form wouldhave negative effects on several systems in the body,causing nuclear damage and alteration of neurotransmitterand enzyme functions.Higher levels of zinc would compound this effect.Furthermore, the very high levels of zinc found in thehippocampus are enclosed in protective membranousvesicles. In vitro experiments would not account for this.In 2 of the 6 patients receiving zinc supplementation, anincrease in libido occurred, necessitating the prescription ofcyproterone acetate. A rise in libido following zincsupplementation has previously been noted in theliterature.DiscussionZinc supplementation unexpectedly did not result in higherplasma zinc levels in all patients. The variable plasma zinclevels found may have reflected either a defect in theabsorption of zinc (unlikely, see below) or immediateredistribution of absorbed zinc into body stores.The 6 AD patients who received oral zinc supplementationdisplayed a steady increase in platelet membranemicroviscosity. This suggests that zinc plays an importantrole in maintaining the patency of the microviscosity ofmembranes in the body. This role could bestructural, inthat zinc may bind to the charged headgroups ofphospholipids in membranes, or produce an atteration ofthe phospholipid composition of the membranes. DriscollandBettge found that dietary zinc deficiency in ratscaused a change in erythrocyte phospholipid composition.Zinc may also protect platelet membranes from decreasedmembrane microviscosity caused by lipid peroxidation,8through the inhibition of free radical reactions.The fact that oral zinc supplementation had a positiveeffect on platelet membrane microviscosity in the presenceof variable plasma zinc levels, indicates that the latter doesnot reflect the zinc concentration present in thesemembranes.Though preliminary, the results counter the claims madeby Bush et al. that zinc adversely affects... cognition...ConclusionZinc supplementation corrected the membranemicroviscosity of platelets in a sample of 6 AD patients.A further ongoing study of 4 patients showed that zincsupplementation resulted in a modest temporaryimprovement in the cognition of all of these patients, asobserved on psychometric testing. This is at variance withBush et al.'s report of rapid cognitive deterioration in ADpatients receiving zinc supplementation. The latter effectmay have been dose-related, thus altering the distribution ofand upsetting the balance of other metals in the body, withnegative consequences. We feel that it may be premature tosingle out zinc as a causal agent in AD.
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.
http://www.ncbi.nlm.nih.gov/pubmed/16327063 (the authors of this article argue that at least in certain cells zinc does not increase phospholipase C activity).
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC43811/ (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.
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:See: http://alzheimersweekly.com/content/zinc-supplement
Came across this article advocating zinc therapy:
International Journal of Alzheimer’s DiseaseVolume 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
AbstractBreakthrough 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:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178199/______________________________________________________And here's a recent and very technical article that may be of interest:
David D. MottRaymond Dingledine
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.http://www.cabdirect.org/abstracts/19911431348.html;jsessionid=A71E9027D61BD6AE6F392F7C54A8B4D7
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) http://biorover.askhermes.org/integrated/BioRoverResults.uwm?diseaseId=47614&searchTerm=Aifm1&resultType=sentence&geneName=p38 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).
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.
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.
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 (http://onlinelibrary.wiley.com/doi/10.1002/biof.1005/abstract?deniedAccessCustomisedMessage=&userIsAuthenticated=false), 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 (http://www.eurekalert.org/pub_releases/2010-04/uoth-adt040110.php). 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.
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.
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.
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.
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.