Galantamine, vitamin E, and specific polyphenols offer the power to …
Break the Bonds of Dementia
For the first time, the combination of galantamine and vitamin E supplementation
has been shown to work synergistically
By Will Block
Perchance he for whom this bell tolls may be so ill,
as that he knows not it tolls for him …
— John Donne,
Devotions Upon Emergent Occasions
he toll of Alzheimer’s disease (AD) continues to grow. Lethal and progressive, AD is an incurable brain disease that slowly destroys the seat of consciousness. As the leading dementia—diseases that abolish the faculty of mind—AD now affects about 5 million in the US. That may not seem like a lot, given the U.S. population of 300 million, but the disease risk increases with age, its greatest known risk factor. And it accelerates with age. Most individuals with the disease are 65 or older, and the likelihood of getting it doubles about every five years after age 65. This means that if you have your sights on living a long time, you need to contend with risk of developing AD, which reaches nearly 50 percent at the age of 85! This astounding figure appears bound to grow as the average age of the population rises, so understanding the basis of cognitive decline is critical and an intervention strategy is required.
The Shock of Losing Memory
In mid-May, I attended a philosophical/political conference in San Diego. It was a renewing experience to meet up with so many agile- and like-minds. It came as a shock when one of the speakers—whose work has been an inspiration for many of those in attendance—announced that he was losing his memory. It seems that he had taken a number of pain killers for a back injury, the result of which was the loss of his ability to remember what he knew and where his thoughts led him. And, as he cautioned us, it was likely to occur at any time. Could it be true, that one of the best minds of our generation was now in the thralls of dementia, and that he could be stopped in his thought-tracks without a moment’s notice?
A shrouded moon overhangs the night profile of San Diego.
Even if you have your sights on
living a long time, the risk of
developing AD reaches nearly
50 percent at the age of 85!
Well, I am saddened to say that his prediction proved accurate, with the most deadening silence in the midst of some of his most exquisite thoughts. As I once wrote, “If freedom is to have a future, we must preserve what we know, and after ourselves, preserve the minds of our teachers. Nothing could be more paramount.” (See
“Saving Our Teachers’ Minds”
in the July 2004 issue of Life Enhancement.)
Vitamin E, Galantamine, and AD
As a possible therapeutic strategy for AD, vitamin E has been shown to prolong the duration of time before hospitalization is required for almost 1 year, presumably by trapping free radicals and thus interrupting the chain reaction that subsequently leads to cellular damage. Furthermore, there is also evidence to show that acetylcholinesterase inhibitors (AChEIs), including donepezil, rivastigmine, and the natural plant alkaloid galantamine, enhance cholinergic function by increasing synaptic acetylcholine concentration, thereby resulting in cognitive benefits and behavioral improvement.
Because both AChEIs and vitamin E operate through different mechanisms, it could be expected that the treatment effects are additive. Yet it is not inconceivable that the substances could interfere with each other. With this in mind, it is surprising that the combination studies that could clarify this relationship have been limited to a retrospective chart review of donepezil and vitamin E, including a comparison with a historical sample of untreated patients. Where are the missing studies?
In a recent letter published in Journal of Clinical Psychopharmacology, a retrospective combination study was reported by Daniel M. Bittner, MD, of the Department of Neurology, University of Magdeburg, Germany and also of the Department of Neurology, University of Ulm, Germany. Consisting of 49 patients with mild to moderate AD, the patients were divided into 2 groups, one that received an AChEI alone (19 males and 10 females, mean age of 67.7 years, with a standard deviation of 8.3 years) and another where AChEI was combined with high dose vitamin E (9 males and 11 females, mean age of 70.1 years, with a standard deviation of 6.8 years).
Daily doses of either of three AChEIs were given—at least 5 mg of donepezil, 6 mg of rivastigmine, or 16 mg of galantamine. Vitamin E intake was at least 500 IU daily (with the mean at 1,805 IU daily). None of the subjects with adequate follow-up was excluded for failure to continue treatment, but in one patient in each group, rivastigmine was changed to donepezil owing to undesirable side effects.
The average MMSE score for patients
on AChEIs and vitamin E
improved for the combination of
galantamine and vitamin E.
In the AChEI alone group, the dosage of rivastigmine was 12 mg daily, whereas in the combination group, it was half the dose, 6 mg daily. There were no additional AD medications used, such as memantine, and no further adverse events were reported during follow-up. At the start of the study, apolipoprotein E (ApoE) genotyping was performed and age, sex, medical history, along with medications and their dosages were recorded.
Tracking Cognitive Changes
Mini-Mental State Examination (MMSE) was recorded at the start and end. The MMSE (aka the Folstein test) is a brief 30-point questionnaire test that is used to screen for cognitive impairment, and commonly used to detect dementia. Moreover, it can be used to estimate the severity of cognitive impairment at some given point in time, with the followup capability to track the course of cognitive changes in an individual over time. Hence, it is an effective way to document an individual’s response to treatment.
To control for possible confounding factors, a stepwise regression analysis was performed. There were no differences in basic demographic data between the two groups with respect to age, sex, ApoE phenotype, type of cholinesterase inhibitor, or time of follow-up.
Galantamine and Vitamin E Found Superior
The mean time of followup for all patients was 14.6 months. For those taking the AChEI alone, the mean was 14.9 months, and for those taking the combination of an AChEI and vitamin E, the mean was 13.9 months. At the start of the treatment, subjects receiving an AChEI alone had slightly better cognition, although this was not judged to be significant. The average MMSE score for patients on AChEIs and vitamin E declined at a significantly lower rate as compared with the group treated with an AChEI alone (see Fig. 1). It actually improved for the combination of galantamine and vitamin E.
Figure 1. Difference in initial and follow-up MMSE (mean [SD]; P = 0.01), dependent on the different cholinesterase inhibitors and treatment groups (P > 0.05).
Dr. Bittner used a forward stepwise regression approach in which independent variables are entered one after another to analyze how much each one adds to the explanation of the dependent variable (MMSE change in follow-up). In a significant model where sex, age, initial MMSE, type of cholinesterase inhibitor, and ApoE were entered, the treatment with vitamin E turned out to be a sufficient predictor.
Until now, vitamin E by itself has not been recommended for the routine treatment of AD. However, these new data provide important evidence that when vitamin E is combined with an AChEI, and especially galantamine, the resulting benefits are significant.
Vitamin E and Galantamine are Synergistic
Although AChEI therapy and vitamin E probably act through different mechanisms, they seem not to interfere with each other but instead act synergistically together to offer additional benefits than each would separately. A possible explanation is that vitamin E prevents anticholinesterase-induced oxidative injury which may be caused by AChEIs. Although the sample size in the Bittner study is small, and thus places limitations on broad generalizations, nevertheless it is the first time that a combination of vitamin E and AChEIs have been compared with AChEIs alone. Previously, only combination therapy with vitamin E and donepezil compared with controls has been investigated. In another recent study, vitamin E and donepezil were compared in mild cognitive impairment, the diagnosis of which can indicate a risk of AD or preclinical AD. In this study, some effects of vitamin E on language and executive functioning could be observed at up to 18 months. However, these effects were only temporary and of small size. However, in another study, no positive impact of vitamin E on brain atrophy rate was observed.
These new data provide
important evidence that when
vitamin E is combined with an AChEI,
and especially galantamine,
the results are significant.
Overall the strength of the current study is the comparison of AChEIs alone versus in combination with vitamin E. To the best of Dr. Bittner’s knowledge, no other study has used this design, let alone demonstrated that combination therapy is superior to AChEI therapy alone. It is important to repeat that neither age, sex, nor ApoE phenotype had any influence on the course of dementia in the study. Unfortunately, given that the study was retrospective and not placebo controlled is a weakness, along with the small sample size.
Naturally Occurring Dietary Polyphenolic
Phytochemicals for the Prevention of AD
Galantamine and vitamin E are not the only nutrients found beneficial for helping to stave off dementia. A recent review discusses other natural approaches to dampen the effects of AD and other dementias. While a number of drugs—including several AChEIs and an NMDA receptor antagonist—have been approved for use, noted the review, there are a variety of side effects and the benefits are relatively modest. But fortunately, extensive research and development investigations are underway to identify other drugs, involving other mechanisms that show effectiveness without undesirable consequences. And at the same time, naturally-occurring dietary polyphenolic phytochemicals are receiving greater attention as complementary possibilities for AD therapy.
The first sign of AD and other
dementias is often the appearance of
subtle and sporadic deficits in
the ability to remember minor
Some of the most promising allies include turmeric (and several of its active ingredients, including curcumin), resveratrol, and green tea catechins (especially epigallocatechin gallate or EGCG), all of which are now thought to have the ability to help prevent AD and other dementias due to their anti-inflammatory, antiamyloid, and antioxidative properties. At the same time, these polyphenolic phytochemicals activate an adaptive cellular stress response called neurohormesis, a means by which nerve cells are induced to prepare themselves to meet minor stress and prevent disease. A neurohormetic activity imposes a mild stress on cells, thereby enhancing their ability to deal with greater stresses.
The Right Vitamin E:
(From an interview “Maintain your Brain the Durk Pearson & Sandy Shaw Way,” originally appearing in the May 2004 issue of Life Enhancement).
Amyloid-Beta and Antioxidant Vitamins E and C
Durk In addition, there are epidemiological data showing that people who eat larger amounts of vitamin E and vitamin C in their diets have a lower incidence of Alzheimer’s disease (age-adjusted, of course) (Engelhart et al. 2002). Dietary E reduces the incidence of Alzheimer’s in those without the APOE-4 gene, which is a risk factor for Alzheimer’s (Morris et al. 2002). For the most part, supplement studies have not shown consistently positive results, probably because the durations of supplement use were too short. For the exceptions, see Sano et al. 1997 for vitamin E, and Morris et al. 1998 for vitamin C. No benefits were observed with a C + E supplement in Masaki et al. 2000. On the other hand, a very strong protective effect was found in those who took relatively high doses of both C and E supplements, but not in those who took only C or only E (Zandi et al. 2004). This study found an adjusted Alzheimer’s incidence odds ratio for C + E supplement users of 0.22 (95% confidence interval of 0.05 to 0.60). Theoretically, a combination of antioxidants might work better.
A free radical is a molecule with an unpaired electron. In order to get rid of that free radical, you have to go through a step-wise process of transferring the unpaired electron from one molecule to another, and another, each having less energy, each being less reactive and having a longer lifetime, until you can finally get rid of it by pairing it up with another long-lived free radical. So in general you need a combination of free radical scavengers to get the results you want. Otherwise, if you just have one, it ends up being bottlenecked there. For example, if you have vitamin E alone, you end up with a tocopheryl radical.
Sandy You want to hand that tocopheryl radical’s unpaired electron off to another antioxidant, but if you don’t have adequate quantities of other antioxidants, you’re going to have a bunch of tocopheryl radicals hanging around. And they do damage as well—not as much damage as the radicals they’ve quenched, but they still need to be eliminated.
Durk Theoretically, you’d expect that vitamin E and vitamin C together would do a lot better than either E or C alone. In addition to having C in our formulation, the type of E we have is rather special and expensive: it’s D-alpha-tocopheryl succinate. Now, the reason we use the D-isomer alone rather than the usual D,L mixture is that the blood-brain barrier is remarkably picky, and there are stereospecific transporters that more readily carry the D-isomer of vitamin E across the barrier than the L-isomer. The D- and L-isomers are both perfectly good antioxidants—in vitro (in a test tube), you won’t see any difference—but you’ve got to get vitamin E into the brain, and the D-isomer is best in that regard. Also, we use the succinate ester rather than the less expensive acetate ester, because there are specific transporters for succinate in the blood-brain barrier, as well as in membranes around the mitochondria; those are the free radical hotbeds of activity, where you especially want to deliver antioxidants. (See Meydani 1995 for a review on vitamin E.)
- Engelhart MJ, Geerlings MI, Ruitenberg A, van Swieten JC, Hofman A, Witteman JC, Breteler MM. Dietary intake of antioxidants and risk of Alzheimer disease. JAMA 2002 Jun 26;287(24):3223-9.
- Masaki KH, Losonczy KG, Izmirlian G, Foley DJ, Ross GW, Petrovitch H, Havlik R, White LR. Association of vitamin E and C supplement use with cognitive function and dementia in elderly men. Neurology 2000 Mar 28;54(6): 1265-72.
- Meydani M. Vitamin E. Lancet 1995 Jan 21;345(8943):170-5. Review.
- Morris MC, Beckett LA, Scherr PA, Hebert LE, Bennett DA, Field TS, Evans DA. Vitamin E and vitamin C supplement use and risk of incident Alzheimer disease. Alz Dis Assoc Disord 1998 Sep;12(3):121-6.
- Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Aggarwal N, Wilson RS, Scherr PA. Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. JAMA 2002 Jun 26; 287(24):3230-7.
- Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, Woodbury P, Growdon J, Cotman CW, Pfeiffer E, Schneider LS, Thal LJ. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. NEJM 1997 Apr 24;336(17):1216-22.
- Zandi PP, Anthony JC, Khachaturian AS, Stone SV, Gustafson D, Tschanz JT, Norton MC, Welsh-Bohmer KA, Breitner JC; Cache County Study Group. Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study. Arch Neurol 2004 Jan;61(1):82-8.
In the Beginning …
The first sign of AD and other dementias is often the appearance of subtle and sporadic deficits in the ability to remember minor everyday events. Then, in its later stages with the gradual progression to severe dementia, multiple cognitive and behavioral functions are affected. Basic research has identified many of the pathways and mechanisms that contribute to this devastating disease, the results of which provide increased opportunities for developing new treatments.
The prevalence of AD in
certain regions of India is 4.4-fold less
than in the United States,
implying that a diet rich in turmeric
might be a causal factor for
reduced AD risk in aged Indians.
Among these options are certain naturally occurring phytochemicals, compounds that have been the subject of increasing interest on the part of consumers and manufacturers.
These have been brought to the public’s attention from numerous epidemiological studies that suggest that the consumption of polyphenolic phytochemical-rich foods or beverages can help to prevent certain neurological diseases, including AD and other dementias.
Phytochemicals are plant-derived chemical compounds, many of which have been shown to help prevent certain chronic diseases, such as cancers and cardiovascular diseases, by reducing or correcting cellular dysfunctions. Within this group, the polyphenolic phytochemicals possess the highest level of antioxidant properties. And while these properties are clearly important, many studies have demonstrated that there are other explanations for their protective cellular effects.
Based on epidemiological studies indicating preventive effects for AD and other dementias, interest has emerged from among these polyphenolic phytochemicals in turmeric (and its active components such as curcumin), resveratrol, and green tea catechins (especially EGCG).
The rhizome of turmeric (Curcuma longa)—containing an imposing number of active compounds, including curcumin—has found use as a food preservative and spice that gives a characteristic flavor to Indian curries. It has been reported that the prevalence of AD in people 70–79 years of age in certain regions of India is 4.4-fold less than in the United States, implying that a diet rich in turmeric (and consequently curcumin) might be a causal factor for reduced AD risk in aged Indians. In vitro and in vivo evidence indicates abundantly that curcumin has antiamyloidogenic, antioxidative, and anti-inflammatory properties that carry the potential to prevent AD. Other in vitro studies show that curcumin can dose-dependently inhibit the formation and extension of neurotoxic amyloid-beta (aβ) fibrils representing an attractive therapeutic strategy for the treatment of AD. It may be that the structure of curcumin is able to specifically bind free aβ and subsequently inhibit the formation of fibrils, or that it might destabilize the beta-sheet-rich conformation of aβ in the fibrils.
Antioxidant Activity and Stress Protection
Curcumin also exhibits significant antioxidant activity, which is why it has found use as a preservative. It is surprising that curcumin has been found to be a much stronger free radical scavenger than vitamin E, and it serves this function to protect brain tissue from nitric oxide-based radicals and lipid peroxidation. Curcumin can also scavenge hydroxyl radicals, thereby preventing oxidative damage of DNA in mouse connective tissue cells. In other in vitro experiments, curcumin (along with its metabolites, also found in turmeric) was shown to bind copper and iron ions, redox-active metals that exacerbate aβ aggregation or cause subsequent oxidative damage in the AD brain. Thus, curcumin and its metabolites may help prevent reactive metal-mediated aspects of AD pathogenesis. It is also worthy of comment that copper-curcumin complexes behave as radical scavengers and exhibit endogenous antioxidant-mimetic properties. Curcumin also helps restore glutathione, another endogenous antioxidant, in the brain while it induces an antioxidant enzyme that is a stress protector in brain tissue, thus serving an anti-degenerative function in AD pathogenesis.
Because the aβ-mediated
inflammatory process in
the pathogenesis of AD
is so devastating,
the anti-inflammatory property of
curcumin could prove beneficial for
the prevention or treatment of AD.
Other evidence for curcumin’s antioxidant properties is provided by studies using an AD mouse model, in which curcumin reduced brain levels of oxidized proteins containing carbonyl groups. Curcumin also suppresses the activity of the transcription factors NF-jB (a proinflammatory family of transcription factors) and activator protein-1, and regulates inflammatory responses. It is also capable of blocking the induction of inducible nitric oxide synthase, possibly by inhibiting NF-jB activation.
On yet another front, curcumin inhibits lipoxygenase and cyclooxygenase-2 (COX-2), which cause the synthesis of pro-inflammatory molecules. Returning to its effect on aβ, curcumin has been found to abolish aβ-induced expression of immune system signalling molecules that may result in inflammation.
Because the aβ-mediated inflammatory process in the pathogenesis of AD is so devastating, the anti-inflammatory property of curcumin could prove beneficial for the prevention or treatment of AD. Altogether, the anti-AD effects of curcumin have been shown in several animal models of AD. When fed to aged mice, even low doses of curcumin reduced aβ plaque levels in the brain.
Microscopy has shown that curcumin crosses the blood-brain barrier to target senile plaques and disrupt existing plaques in these mice. In a rat model, the preventive effects of curcumin are apparent when various human aβs have been infused into the brain tissue of aged female rats which would normally produce AD-like aβs, but instead the animals were protected by curcumin and exhibited better memory function compared to rats not receiving curcumin. In rats fed curcumin, there was an indication of improved synaptic transmission, suggesting that curcumin might prevent aβ-mediated synaptic deficits. Altogether, these study observations raise the banner of hope that dietary supplementation with curcumin could be an effective preventative against AD.
Resveratrol, about which we have written extensively, is a polyphenolic phytochemical found in grapes, red wine, and berries, and which possessed a wide range of biological and pharmacological activities. Starting with epidemiological studies, there is clear evidence that an inverse relationship between wine consumption and the incidence of AD exists. This has led to speculation that resveratrol might be the cause of some of these beneficial effects in AD patients. As is the case with curcumin, resveratrol easily crosses the blood-brain barrier and penetrates into brain tissue. In both in vitro and in vivo studies, resveratrol has been reported to have potent neuroprotective properties, and recent data indicate that it can reduce neuronal cell death and mitigate cerebral damage after ischemia/hypoxia, trauma, and excitotoxicity.
Reducing Amyloid Formation
On another front, resveratrol is reported to possess anti-amyloidogenic activity, reducing aβ peptides in several cell lines. Resveratrol has also been found to suppress the level of aβ by modulating the protein complexes within cells. It also protected neuroblastoma cells and hippocampal neurons from aβ-induced toxicity, effects that were associated with resveratrol-induced activation of protein kinase.
Experimental evidence suggests that
resveratrol may block oxidative
stresses that are causal in the
pathogenesis of AD. This alone makes
resveratrol a promising therapeutic
agent to prevent or treat AD.
Experimental evidence suggests that resveratrol may block oxidative stresses that are causal in the pathogenesis of AD. This alone makes resveratrol a promising therapeutic agent to prevent or treat AD. Continuing, resveratrol can scavenge free radicals while protecting neurons and microglia. When rat sympathetic nervous system tumor cells were pretreated with resveratrol, the result was reduced aβ-induced intracellular reactive oxygen species (ROS) accumulation, which subsequently suppressed the activation of the proinflammatory transcription factor NF-jB.
Resveratrol also up-regulates cellular antioxidants, including glutathione, induces the gene expression of protective enzymes, and protects against oxidative and electrophilic injury. Like curcumin, resveratrol potentiates the neurohormetic pathway in neuronal cultures, thereby enhancing a neuron’s ability to deal with greater stresses.
In the brain of rats, resveratrol exerts a neuroprotective action against induced oxidative stresses. Chronic administration of resveratrol also significantly reduces the elevated levels of malondialdehyde, a marker for oxidative stress, in these rats. Resveratrol also reduces neuronal cell death and suppresses activation of astrocytes and microglia.
In an earlier study, resveratrol was found to suppress tumor necrosis factor and nitric oxide production in a mouse microglial cell line by inhibiting the activation of a proinflammatory transcription factor and p38 mitogen-activated protein kinase phosphorylation. (p38 mitogen-activated protein kinase are a class of mitogen-activated protein kinases which are responsive to stress stimuli.) Resveratrol has been shown to block the expression of the proinflammatory COX-2 and inducible nitric oxide synthase, possibly by inhibiting activation of the proinflammatory transcription NF-jB factor.
And that’s not all. Resveratrol significantly diminished lipopolysaccharide-induced free radical formation and the expression of the most important and terminal synthase responsible for prostaglandin E2 synthesis in activated microglial cells. Even low concentrations of resveratrol considerably reduced the production of a specific prostaglandin that is a reliable indicator of free radical generation. The neuroprotective effects of resveratrol are thought to be due in part to the lessening of neuroinflammatory responses.
GREEN TEA CATECHINS
The consumption of catechins—a group of polyphenolic antioxidant plant metabolites found in green tea and other foods—has been associated with a wide variety of health benefits. As with turmeric and resveratrol, green tea catechins readily penetrate the brain, and have been increasingly found to proffer neuroprotective actions. They are reported to serve a variety of biological roles, including activation of mitogen-activated protein kinase, protein kinase C, antioxidant enzymes and survival genes, and also to help control calcium homeostasis and amyloid precursor protein (APP) processing.
Protecting Neurons from aβ-Induced Damages
In vitro studies demonstrate that green tea extract probably protects neurons from aβ-induced damages, and that EGCG, a major catechin isolated from the polyphenolic fraction of green tea, reduces aβ generation while decreasing aβ levels and plaques in AD mice. As well, EGCG elevated the activity of enzymes that inhibit generation of APP.
Reducing aβ Levels
EGCG was also found to significantly increase the expression of a converting enzyme that inhibits APP activity. In addition, EGCG works to diminish the amyloidogenic aspect of APP processing. Furthermore, EGCG mediates inhibition of aβ generation. Prolonged administration of EGCG to mice suggests that EGCG might reduce aβ levels by suppressing the expression of an isoform of APP. Green tea catechins are also able to inhibit the formation, extension, and stabilization of aβ fibrils. EGCG has been shown to efficiently inhibit aβ fibrils by directly binding to unfolded polypeptides, possibly through helping to stabilize hydrogen bonds.
Overall, the antioxidant properties of catechins are more potent than those of α-tocopherol or vitamins C and E together. Catechins exert their antioxidative activity by chelating metal ions, including iron and copper, and preventing the generation of potentially damaging free radicals. It has been suggested that using EGCG chelation to reduce the free iron pool might suppress aβ formations. Catechins may also help prevent oxidative DNA modifications. In addition, EGCG scavenges ROS and inhibits lipid peroxidation, and in cells exposed to aβ, it decreases malondialdehyde levels and caspase activity, protecting against aβ-induced apoptosis and enhancing the survival of neurons in the hippocampus.
EGCG also reduces aβ-induced oxidative stress in vivo, thus lowering hippocampal lipid peroxide in the brains of rats. EGCG inhibits the activation of pro-inflammatory markers, and consequently lessens the production of two pro-inflammatory interleukins and vascular endothelial growth factor in human astrocytoma cells. It also suppresses the inflammatory activities of various cytokines and reduces aβ-induced COX-2 expression and prostaglandin E2 production.
Then EGCG inhibits induced microglial activation and protects against inflammation-mediated neuronal injury. It modulates aβ-mediated tau pathology in mice, reducing potentially toxic soluble phospho-tau isoforms. Furthermore, in a recent study, heat-shock protein (HSP) 90 inhibitors were found to reduce the levels of soluble phospho-tau isoforms and EGCG has been found to directly bind HSP90 and inhibit its activity; thus, EGCG might modulate the level of phospho-tau through the inhibition of HSP90.
Better Memory with Green Tea
There is little question that green tea catechins affect memory function positively. For example, EGCG reduces cognitive impairment in mice, and when supplied to the drinking water of rats for 5 months, there was less memory impairment following the injection of human aβ than those supplied normal drinking water. Also, tea catechins ameliorated hippocampal neuronal damage and memory impairment demonstrating a benefit for cerebral ischemia. With all this to consider, treatment with green tea catechins, and especially EGCG, may be a viable therapeutic approach for treating AD-like brain pathologies and associated cognitive impairment.
Finally, while no clinical trials of curcumin, resveratrol, or green tea catechins in AD have been completed, all of these nutrients are generally accepted as safe at anything short of very high levels.
One study found that doses up to 8 g per day of curcumin were well tolerated, and that higher doses were not tolerated simply due to the bulk of the agent. Given that there are currently so many ongoing clinical trials, conclusions on the effectiveness, dose-efficacy, and side effects will be forthcoming in the near future.
Turmeric, curcumin, resveratrol, and EGCG do not merely exhibit potent antioxidative and anti-inflammatory properties, they act to scavenge radicals and regulate inflammatory responses. Also, they readily cross the blood-brain barrier to act on specific targets in neural tissue that have been implicated in the pathogenesis of AD.
Turmeric, curcumin, resveratrol, and
EGCG do not merely exhibit potent
antioxidative and anti-inflammatory
properties, they act to
scavenge radicals and regulate
Perhaps even more important, these polyphenolic phytochemicals reduce the generation of neurotoxic aβ, along with activating endogenous pro-survival pathways, including genes that help to enhance cellular defense mechanisms, which may protect the brain against aβ proteins and deposition of plaques.
It is also possible that these phytochemicals exert a protective effect against other neurodegenerative diseases including Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Curcumin inhibits the aggregation of α-synuclein, the protein involved in the pathogenesis of Parkinson’s. Resveratrol, as evidenced by its ability to protect cells against the toxicity of mutant huntingtin protein in experimental models may help with Huntington’s too. EGCG modulates the early events in huntingtin misfolding and reduces toxicity in Huntington disease models. Then, both resveratrol and EGCG protect motor neurons against an ALS-associated mutation of superoxide dismutase 1. ALS is Lou Gehrig’s disease.
From what we currently know,
dietary polyphenolic phytochemicals
offer the promise of safety and
low expense, along with
ready bioavailability as
prophylactic agents for AD and
other neurodegenerative diseases.
In our final comments, polyphenolic phytochemicals are for the most part innocuous and neuroprotective. They are derived from common food sources, unlike NSAIDs and anti-degenerative drug molecules, which always, even after extensive testing, hold out the possibility of significant safety concerns. From what we currently know, dietary polyphenolic phytochemicals offer the promise of safety and low expense, along with ready bioavailability as prophylactic agents for AD and other neurodegenerative diseases. The potential of this class of compounds is very great.
- Bittner DM. Combination therapy of acetylcholinesterase inhibitor and vitamin E in Alzheimer disease. J Clin Psychopharmacol 2009 Oct;29(5):511-3.
- Milatovic D, Gupta RC, Aschner M. Anticholinesterase toxicity and oxidative stress. Scientific World Journal 2006;6:295-310.
- Klatte ET, Scharre DW, Nagaraja HN, et al. Combination therapy of donepezil and vitamin E in Alzheimer’s disease. Alzheimer Dis Assoc Disord 2003 Apr-Jun;17(2):113-6.
- Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. NEJM 2006;352:2379-88.
- Jack CR Jr, Petersen RC, Grundman M, et al. Longitudinal findings from the vitamin E and donepezil treatment study for MCI. Neurobiol Aging 2008;29:1285-95.
- Kim J, Lee HJ, Lee KW. Naturally occurring phytochemicals for the prevention of Alzheimer's disease. J Neurochem 2010 Mar;112(6):1415-30.
- Ganguli M, Chandra V, Kamboh MI, Johnston JM, Dodge HH, Thelma BK, Juyal RC, Pandav R, Belle SH and DeKosky ST. Apolipoprotein E polymorphism and Alzheimer disease: the Indo-US Cross-National Dementia Study. Arch Neurol 2000;57:824–80.
Will Block is the publisher and editorial director of Life Enhancement magazine.