Galantamine Can Sharpen Your Mental Edge
     It has the edge over its competitors in the Alzheimer's arena
        by Will Block

The Winter Olympics are over now, but who can forget the thrills and chills provided by those great young athletes, defying gravity and death to perform feats of fantastic skill and courage? Some won medals, most did not. And what decided the outcomes? In most events, just a few tenths or even hundredths of a second! Think about that. Clearly, all the top-ranking contestants in any given event had essentially equal physical abilities, the result of natural talent and years of grueling training.

Then what really separates the winners from the losers? It's not so much the metal edge of a ski or skate as it is the mental edge upstairs - that indefinable something extra that gives the chosen few the ability to prevail where others falter. Ask any athlete at that level of the game, and he or she will say that it's mostly a mind game, to be won or lost more by the brain than by the bones and muscles.

The Tragedy of Alzheimer's Disease

Fast-forward half a century or more. Those splendid young bodies now show the many signs of aging we are all too familiar with. Some are still in pretty good shape, all things considered, but some are downright decrepit, the result of unwise lifestyle choices or sheer bad luck.

But what about the minds that reside in those bodies? Is the gleaming mental edge of youth still there, or has it too rusted away? Sad to say, it's a statistical certainty that some of those erstwhile athletes will have Alzheimer's disease. They may have a hard time remembering that they ever were athletes (or even, perhaps, that they were once president of the United States). They will have difficulty remembering the names of their family and friends, let alone learning a new name.

They will be unable, eventually, to function in the activities of daily living - making a phone call or cooking an egg or, perhaps, finding their way home after a walk around the block. Their behavior will take strange and disturbing turns, such as endless fidgeting or pacing, being uncooperative, and having delusions.

They will cause their family and friends consternation and great sorrow. Perhaps their loved ones will already have largely abandoned them to professional caregivers who know how to deal with Alzheimer's disease. What a tragedy that the glories of their youth should come to so pitiful an end.

Remember Galantamine?

But wait - why should any of that happen half a century from now? God willing, such occurrences will be but a distant memory in the sharp, bright minds of those elderly athletes as they think about their own elders (us). Looking back, they will probably marvel at how much progress had been made since the quaint old days of the twentieth century. Perhaps, if they're up on their science, they will remember something called galantamine that played an important role along the way.

If they're really up on their science, they may remember that what set galantamine apart from its competitors in the fight against Alzheimer's disease was its edge - that extra something it brought to the arena, something the others didn't have, something that made galantamine the champion in its time. That's something any great athlete can surely relate to.

What Does Galantamine Do?

So what is galantamine's edge? We'll get to that soon. First, however, let's see what galantamine is and what it does. Galantamine is a chemical compound found in certain flowers, such as the snowdrop, daffodil, and spider lily. Thus, it is a natural substance, and it can be used as a dietary supplement - although since 2001 it has also been sold as a prescription drug (Reminyl^®) for the treatment of Alzheimer's disease.  The other Alzheimer's drugs on the market are synthetic compounds not found in nature.  The two leading ones, donepezil and rivastigmine, have almost completely replaced an earlier drug, tacrine, because they are largely (but not totally) free of tacrine's dangerous side effects.

What all these compounds have in common is that they inhibit the action of acetylcholinesterase, an enzyme that breaks down acetylcholine (ACh), one of the body's most important neurotransmitters. The actions mediated by ACh are collectively called cholinergic function, and a deficit in cholinergic function (i.e., a deficit in ACh or in its effectiveness) in certain parts of the brain is an early and consistent neurological feature of Alzheimer's disease.

As the disease progresses, there is a relentless decline in cognitive function, accompanied by increasing behavioral disturbances. Memory problems, at first subjective, are an early and often ambiguous symptom; if it really is Alzheimer's and not the much less serious age-related memory impairment (which affects everyone to some degree), the memory problems become undeniable and ultimately debilitating.

The Importance of Nicotinic Receptors

Thus, the importance of acetylcholine can hardly be overestimated. And if the problem is too little ACh or an impairment of its effectiveness, an obvious solution would be to increase the levels of ACh. Theoretically, this can be done through stimulation of ACh synthesis by ACh precursors, such as choline or lecithin. In practice, however, this method has shown only minimal efficacy against Alzheimer's. A much better strategy - and the one that has proved by far the most successful to date - is to inhibit the action of acetylcholinesterase, the enzyme that breaks down our ACh molecules. Galantamine does this very effectively - but so do donepezil and rivastigmine.

Thus galantamine has no advantage, right?  Wrong.  It turns out that a serious limitation of the conventional drug therapies is "drug tolerance" - meaning that the body becomes so accustomed to the drug's presence that its efficacy gradually erodes, and it takes more and more of the drug to have an effect.  But there is obviously a limit on how much of the drug one can take, so the inevitable result of drug tolerance is further progression of the disease. This problem has led researchers to look for an agent that has more than one mode of action.

There is, in fact, yet another way to improve cholinergic function.  It is to enhance the activity of certain ACh receptors, called nicotinic receptors, at the brain's synapses (the junctions between adjacent neurons).  Doing that makes the ACh molecules that are already there more effective in transmitting neural impulses; it's the functional equivalent of having more ACh molecules there in the first place. Galantamine does this very effectively - but donepezil and rivastigmine do not.¹

The Winning Edge Revealed

Aha! There's the winning edge - that extra something that galantamine brings to the Alzheimer's arena that makes it the superior agent.  The importance of this edge can be appreciated when we realize that nicotinic receptors play a fundamental role in cholinergic function, and thus in memory and learning.¹  Furthermore, the indirect mechanism by which galantamine stimulates these receptors to increased efficiency does not lead to a progressive desensitization of the receptors to ACh - a problem that occurs with compounds that stimulate the receptors directly by mimicking the action of ACh itself.²  

There's more. Studies on the brains of old rats have shown that galantamine protects nicotinic receptors from deterioration with age, and it actually increases the overall number of nicotinic receptors of a certain key type (there are many types).³  This is highly significant, because in humans the number of nicotinic receptors declines in Alzheimer's disease - specifically, in regions of the brain involved in memory and learning tasks that are impaired by the disease.^4,5  This decline thus correlates well with the severity of the disease.^6,7

Galantamine Preserves Cognitive Function

Studies have shown that, over the course of one year, there is a clear and significant decline in cognitive function in patients with Alzheimer's disease.⁸  For a treatment to be regarded as successful, therefore, it is not necessary that it be able to reverse the course of the disease (a tall order); success is achieved if the treatment can halt the decline and maintain baseline levels of cognitive function, i.e., the levels that prevailed when the treatment was begun.

In a recent review article on current treatments for Alzheimer's, the author cites evidence for the success of galantamine in this regard from three randomized, double-blind, placebo-controlled studies of up to six months' duration.⁹  In these studies, galantamine actually went one better than maintaining baseline levels of cognitive function: it significantly improved them. By contrast, in the control groups taking placebo, cognitive function declined significantly, as expected.

The author of the review also describes two 12-month studies in which galantamine treatment (24 mg/day) was again successful, albeit less dramatically so.  For the most part, cognitive function remained unchanged over the course of these studies - a definite success, since normally a decline would be expected - but in some measures it showed a less-than-expected decline (modest success), and in others it showed some improvement.

Galantamine Alleviates Caregivers' Burden

The two 12-month studies evaluated not just cognitive function but also caregivers' burden, i.e., the practical impact of the disease, in terms of time and effort required, on those charged with caring for the patients. In both studies, the overall caregivers' burden remained unchanged over the course of the study for those in the galantamine group. By contrast, there was a significant increase (as expected) in the burden on those caring for patients in the control group.

Galantamine Preserves Ability to Function in Daily Living

The author of another review article cites four randomized, double-blind, placebo-controlled studies that encompassed the effects of galantamine on functional ability (as opposed to cognitive function) in Alzheimer's disease.¹⁰  In three of these studies, galantamine showed significant benefits on an index called Activities of Daily Living (ADL), as measured by standardized tests. These studies were of three, five, and six months' duration, and the dosage of galantamine used ranged from 16 to 32 mg/day, with a 24-mg/day dose included in each study.

In the fourth study, no benefits from galantamine were seen after six months of treatment (no difference between galantamine and placebo), but when the study was extended to 12 months, it was found that patients receiving 24 mg/day of galantamine had maintained their baseline levels on the ADL scores, whereas those on placebo had suffered a significant decline.

Galantamine Preserves Behavioral Stability

One of these studies also evaluated behavioral symptoms associated with Alzheimer's disease, and here again, galantamine (16 and 24 mg/day) showed a distinct benefit: maintenance of baseline values on a standardized test over a five-month period, while the control group showed a significant decline.  The researchers also studied the effect of these behavioral patterns on caregivers' burden, and they found (not surprisingly) that a favorable outcome in behavior translated to a decreased burden on the caregivers.

It has been suggested that the positive results of galantamine in slowing the progression of Alzheimer's disease may be due in large part to its effects on the brain's nicotinic receptors, particularly because this mechanism is not subject to the tolerance problem that affects donepezil and rivastigmine in their role as acetylcholinesterase inhibitors.^2,11 There's that winning edge again.

Galantamine Covers All Bases

Galantamine offers the dual-mode action for boosting cholinergic function: it inhibits the enzyme acetylcholinesterase, and it modulates the brain's nicotinic receptors. The recommended daily serving ranges from a low of 4 to 8 mg of galantamine to begin with to a maximum of 24 mg, depending on the individual's response.  Galantamine thus covers all bases in providing the means to enhance the levels and effectiveness of your acetylcholine. Compared with its competition, galantamine has the winning edge. It deserves a gold medal!

References             www.AlzheimersTreatments.com

1. Albuquerque EX, Santos MD, Alkondon M, Pereira EFR, Maelicke A. Modulation of nicotinic receptor activity in the central nervous system: a novel approach to the treatment of Alzheimer disease. Alzheimer Dis Assoc Disord 2001;15 Suppl 1:S19-25.
2. Maelicke A. Allosteric modulation of nicotinic receptors as a treatment strategy for Alzheimer's disease. Dement Geriatr Cogn Disord 2000;11 (Suppl1):11-8.
3. Barnes CA, Meltzer J, Houston F, Orr G, McGann K, Wenk GL. Chronic treatment of old rats with donepezil or galantamine: effects on memory, hippocampal plasticity, and nicotinic receptors. Neuroscience 2000;99:17-23.
4. Whitehouse PJ, Martino AM, Antuono PG, et al. Nicotinic acetylcholine binding sites in Alzheimer's disease. Brain Res 1986;371:146-51.
5. Schröder H, Giacobini E, Struble RG, Zilles K, Maelicke A. Nicotinic cholinoreceptive neurons of the frontal cortex are reduced in Alzheimer's disease. Neurobiol Aging 1991;12:259-62.
6. Nordberg A. In vivo detection of neurotransmitter changes in Alzheimer's disease. Ann NY Acad Sci 1993;695:27-33.
7. Nordberg A. PET studies and cholinergic therapy in Alzheimer's disease. Rev Neurol (Paris) 1999;155:S53-63.
8. Stern RG, Mohs RC, Davidson M, et al. A longitudinal study of Alzheimer's disease: measurement, rate, and predictors of cognitive deterioration. Am J Psychiatry 1994;151:390-6.
9. Tariot PN. Maintaining cognitive function in Alzheimer disease: how effective are current treatments? Alzheimer Dis Assoc Disord 2001;15 Suppl 1:S26-33.
10. Winblad B. Maintaining functional and behavioral abilities in Alzheimer disease. Alzheimer Dis Assoc Disord 2001;15 Suppl 1:S34-40.
11. Coyle JT, Kershaw P. Galantamine, an acetylcholinesterase inhibitor that modulates nicotinic receptors: effects on the course of Alzheimer's disease. Biol Psychiatry 2001;49:289-99.

 

To Avoid Alzheimer's, Get Really Old Alzheimer's researchers have discovered that there is a distinct peak in the age distribution curve for this disease.1 That's a fancy way of saying that if you live long enough without getting Alzheimer's, your chances of getting it will start to decrease rather than continue to increase! This is true, at least, of the residents of Cache County in northern Utah, who are known for their extraordinary longevity. The researchers chose Cache County so as to be able to study large numbers of people who live well into their nineties and beyond. They evaluated 3308 people aged 65 or more as of January 1, 1995. What they found was that the usual accelerating increase in the incidence of Alzheimer's disease in elderly people (a doubling about every five years, as also observed in other studies) starts to level off in the early nineties, reaches a peak value, and then steadily declines. For men, the peak age is 93, and for women it's 97. The disadvantage to women in these results is compounded by the fact that, after the age of about 85, they become several times more susceptible to Alzheimer's than men. Until about 80 years of age, there's only a slight difference between the sexes in this regard. Alzheimer's May Not Be Inevitable These results suggest that Alzheimer's disease is not an inevitable consequence of aging, at least for some segment of the population, which may have reduced vulnerability owing to either genetic or environmental factors. An interesting result of the study, however, was that the peak appeared in the curves even for those men and women who were found to have two copies (one from each parent) of a certain gene called APOE-e4 that is known to be associated with the risk of Alzheimer's. The difference was that the peak appeared more than ten years earlier, reflecting the fact that people with two copies of this gene tend to develop Alzheimer's much earlier than those without the gene. (Those who have just one copy of the gene also tend to develop Alzheimer's earlier, but the effect is not statistically significant.) Two Big Questions Two questions arise: why is there a peak in the curve, and why is there a difference between men and women? The authors suggest that some people may be relatively invulnerable to Alzheimer's, perhaps due to an as yet undiscovered genetic factor. If these people tended to outlive their more susceptible counterparts - as they would, all else being equal - the curve would have to start declining at some point. Another possible explanation is the early death of those who have risk factors for Alzheimer's but who do not have the disease itself. Atherosclerosis, for example, is thought to be such a risk factor.2 It is a leading cause of death (notably from heart attacks and strokes), so people predisposed to this disease tend to die off rather than join the ranks of the very old. By taking their risk factor for Alzheimer's with them to the grave, so to speak, they leave the more elderly surviving population with a depleted risk factor for Alzheimer's, eventually leading to that decline in the curve. The atherosclerosis connection might also explain, at least in part, the gender difference observed in the two curves. It is well known that cardiovascular disease kills men at an earlier age than women, so potential Alzheimer's victims are removed from the male population more expeditiously than from the female population. This would tend to shift the peak in the male curve to an earlier age than that for women. A Healthy Lifestyle Matters The results of this study must be interpreted with caution because of some unusual features of the population of Cache County, Utah. The people there are highly educated, mostly Caucasian, relatively homogeneous, and overwhelmingly Mormon (91%). The last factor is significant because they typically adhere to a healthy lifestyle (including abstinence from tobacco and alcohol) that follows the teachings of their church. It's probably no coincidence that they’re exceptionally long-lived. Thus, one cannot generalize the results of the Utah study to minority groups or to populations with less healthy lifestyles. Nonetheless, they offer an intriguing new insight into the dark heart of Alzheimer's disease. References Miech RA, Breitner JCS, Zandi PP, Khachaturian AS, Anthony JC, Mayer L, for the Cache County Study Group. Incidence of AD may decline in the early 90s for men, later for women: The Cache County study. Neurology 2002;58:209-18. Breteler MM, Bots ML, Ott A, Hofman A. Risk factors for vascular disease and dementia. Haemostasis 1998;28:167-73.

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