Galantamine Does What Others Can’t
Sustained Cognitive Benefits
New study demonstrates that it buys time for victims of Alzheimer’s disease
By Will Block
hen Paul Hamm won the all-around gold in men’s gymnastics at the Olympic games in Athens in the summer of 2004, it was the result of one of the most spectacular comebacks in the history of sport. Having suddenly dropped to 12th place because of a disastrous landing on the vault, and with only two events left to go, he pulled off probably the two greatest performances of his life and squeaked back into 1st place by the slimmest of margins. It was a thrilling finish, and the culmination of a lifelong dream for Hamm.
Comebacks like that are the stuff of legend, and one can only be awestruck by the phenomenal strength and skill of Olympic gymnasts, whether they win or lose. Nowhere else are the amazing capabilities of the human body so clearly evident.
Can the Brain Make a Comeback?
The human brain is marvelous in its own, more subtle, way, and it too is capable of making dramatic comebacks—not just in performance, such as coming from behind to win on Jeopardy, but in functional capacity following some kinds of damage. Witness the astonishing ability of many stroke victims—with good medical care, a lot of hard work, and some luck—to regain the abilities so cruelly taken from them in one devastating moment. Even a damaged brain can repair itself, at least in some ways, under some circumstances.
Unfortunately, those circumstances do not include Alzheimer’s disease, which causes cumulative brain damage and a steady decline in cholinergic function, i.e., mental activities that depend on the neurotransmitter acetylcholine to transmit impulses from one neuron to the next. Most severely impacted by this decline are cognitive functions, such as memory and learning, but other capacities are affected too. Once well underway, this tragic course of events cannot be stopped.* It can, however, be stalled, and even reversed, for a period of time, and that in itself represents a significant advance in the treatment of Alzheimer’s disease.
Galantamine Can Buy Time
We owe this recent advance to the chemical compound galantamine, a natural substance found in certain flowers, such as the snowdrop, the daffodil, and the spider lily. Although galantamine is available as an FDA-approved prescription drug for the treatment of mild to moderate Alzheimer’s disease, it is also available as the nutritional supplement it has been since long before it became a “drug.”
Galantamine differs from the other currently used anti-Alzheimer’s agents in two important ways: (1) it has not just one mode of action, but two distinctly different modes, both of which increase the brain’s cholinergic activity; and (2) it is able not only to stall the decline in cognitive function, but actually to reverse it (to a degree) for some months, thus “buying time” before the patient’s condition eventually declines again to where it was when the galantamine treatment was begun.
These results have been observed in several major clinical trials conducted in the United States and abroad in recent years. A meta-analysis (a thorough, critical, comparative analysis) of all the significant studies on galantamine confirmed its role as a safe and effective treatment for mild to moderate Alzheimer’s disease.
Galantamine Improves Cognitive Function
One of the studies evaluated in the meta-analysis was a randomized, double-blind, placebo-controlled trial that was completed by 779 patients (average age 77) with mild to moderate Alzheimer’s disease. For the 5-month duration of this trial (called USA-10 in the inventory of major galantamine trials), the patients were given a daily dose of either galantamine (8, 16, or 24 mg) or placebo. The 24-mg dose of galantamine tended to give the best results—and they were most encouraging: the patients taking galantamine did significantly better than the controls in terms of cognitive function, performance in the activities of daily living, and behavioral patterns. These measures were evaluated on the basis of three standardized tests:
- ADAS-Cog/11 (Alzheimer’s Disease Assessment Scale, Cognitive Subsection 11), which tests for a variety of cognitive functions, such as memory, attention, learning, language, reasoning ability, and the ability to visualize spatial relationships.
- ADCS/ADL (Alzheimer’s Disease Cooperative Study of Activities of Daily Living), which evaluates the patient’s ability to cope with ADLs such as bathing, dressing, eating, using household appliances, and managing money.
- NPI (Neuropsychiatric Inventory), which assesses the frequency and severity of symptoms in ten behavioral domains: aberrant motor behavior, agitation/aggression, anxiety, apathy, delusions, disinhibition, dysphoria, euphoria, hallucinations, and irritability/lability.
For inclusion in the study, patients had to have had a history of cognitive decline that was gradual in onset and progressive for at least 6 months, with a diagnosis of probable Alzheimer’s disease. Note the word “probable.” Because all types of dementia have some features in common, and because different types can coexist in one patient, it can be very difficult to make a correct diagnosis. In this regard, the requirements for gradual onset and steady progression of the condition served to rule out (as much as possible) the second and third most common forms of dementia, called Lewy body dementia and vascular dementia, respectively.
Walking Can Help Keep You Mentally Sharp
You’ve heard it before, but hear it again: brisk walking several times a week is one of the best things you can do for your health and well-being. Among the almost endless list of benefits from brisk walking is that it stimulates the circulation, which is good for your heart and, come to think of it, for every other organ and tissue in your body as well. Remember especially that what’s good for your heart is also good for your brain. Both organs depend critically on the ability of your blood vessels to supply them with enough oxygen, glucose, and other nutrients they need to perform their rather important, energy-intensive functions.
Numerous studies, ranging from small clinical trials to comprehensive epidemiological surveys, have demonstrated that more physical exercise means better cognitive function and a reduced risk for cognitive decline. A new epidemiological study has now added more weight to that already solid conclusion. Researchers at Harvard Medical School and the Erasmus Medical Center in Rotterdam, the Netherlands, conducted a statistically powerful and sophisticated analysis of the exercise habits and cognitive health of 18,766 older American women (all of them nurses), aged 70–81, over the period 1986–2003.
The researchers found, as expected, that the women who exercised the most were the least likely to have chronic degenerative diseases, such as heart disease and diabetes, and they were the least likely to have cognitive impairment of almost any kind. The data indicated that, in the authors’ words, “… the apparent cognitive benefits of greater physical activity were similar in extent to being about 3 years younger in age and were associated with a 20% lower risk of cognitive impairment.”
Among the many forms of exercise the women engaged in, the authors singled out walking for special emphasis because of its effectiveness despite being so easy to do, even for most older people. They pointed out that walking the equivalent of at least 1 1/2 hours per week at a pace of about 2–3 miles per hour was associated with better cognitive performance.
So … walk! It will make you feel better, live longer, and stay sharper. And the sharper you are, the likelier you are to appreciate the value of nutritional supplements in giving you yet another edge in your pursuit of life enhancement.
- Weuve J, Kang JH, Manson JE, Breteler MMB, Ware JH, Grodstein F. Physical activity, including walking, and cognitive function in older women. JAMA 2004;292(12):1454-61.
Other Dementias Progress Differently
A hallmark of dementia with Lewy bodies is its sporadic nature, in which the patient has good days of relative clarity alternating with the more common bad days of forgetfulness and confusion. Like all dementias, the disease is progressive, but it’s a somewhat bumpy ride down, in contrast to the smoother ride characteristic of Alzheimer’s.
Vascular dementia is often (but not necessarily) associated with a stroke or a series of ministrokes, each of which tends to produce a sudden, sharp drop in cognitive function, so here the road down is irregular too, but in a different way, somewhat like a staircase with uneven steps.
Galantamine—from the flower to the bottle.
As further insurance against accidentally enrolling patients with vascular dementia, all patients were required to provide a CT or MRI brain scan taken during the preceding 12 months. This enabled the researchers to check for any signs of stroke or other evidence of active cerebrovascular disease.
Researchers Face Ethical Dilemma
Knowing that all the patients in the study probably had Alzheimer’s disease, which is invariably fatal, the researchers faced an ethical dilemma: how long could they give some of the patients placebo instead of galantamine, denying them the benefits of the real treatment and thereby perhaps unnecessarily hastening their inevitable demise? (Bear in mind that, by the double-blind nature of the study, neither the researchers nor the patients knew who was getting what while the study was underway, and the two groups of patients had been selected for either galantamine or placebo on a purely random basis.)
The answer was 6 months, according to bioethicists whose job it is to wrestle with such wrenchingly difficult questions and arrive at reasonable compromises. In this case, the researchers chose to terminate the placebo-controlled phase of the trial at 5 months, after which all the patients, if they wished, could receive galantamine on an “open-label” (unblinded) basis, i.e., they would now know they were receiving it (although they would still not know whether or not they had been receiving it before).
Thus, the patients who had already been on galantamine would continue on galantamine, and the patients who had been on placebo would start taking galantamine—meaning that they would be coming from behind, so to speak, and trying to catch up with their more fortunate counterparts. The question was, could they do it, and in any case, how long would the benefits of galantamine last?
Galantamine’s Benefits Are Sustained Long-Term
Figure 1. Schematic diagram of open-label extension study design. GAL = galantamine; PLA = placebo. From Ref. 5.
That question was the focus of the open-label extension of the original (USA-10) study. Actually, the researchers divided this extension into two phases: (1) a 6-week “washout” phase (called USA-11) with galantamine treatment continued for some patients but not for others, so as to observe the effects of galantamine withdrawal in those who had been receiving it; and (2) a 12-month phase (called USA-12) in which all patients (including those who had previously been on placebo) received galantamine at 24 mg per day (see Figure 1). Thus, with the original study having lasted 5 months and the combined extension phases lasting 13 1/2 months, the total period covered by the two studies was 18 1/2 months. A total of 699 patients enrolled in the open-label study, and 468 of them (67%) completed it.
The principal results of this study (the 18 1/2-month total) were the following:
- All patients who were on galantamine at the outset showed immediate, substantial gains in cognitive performance (ADAS-Cog/11 scores), which peaked after about 5 months. Those who remained on galantamine during the washout phase declined slowly during the subsequent open-label phase, crossing the baseline level at month 14 of the 18 1/2-month study.
- Those patients who were on galantamine at the outset but who were placed on placebo during the washout phase showed immediate, substantial declines in cognitive performance during that period and did not recover to the level of the all-galantamine group until month 9. They then declined at a similar rate, crossing the baseline level at month 14.
- Patients who were on placebo at the outset declined in cognitive performance until they were switched to galantamine; they then showed immediate, substantial gains similar to those of the galantamine group at the outset. They caught up to the galantamine group by month 9 and declined at a slightly faster rate thereafter, crossing the baseline level at month 12.
- There were no statistically significant differences in long-term (18 1/2 months) cognitive benefits among any of the treatment groups.
- Patients treated with galantamine experienced some benefits in functional ability (ADCS/ADL scores) vis-à-vis those in the placebo group, in that their rate of decline was significantly slower for about 12 months. After 18 1/2 months, however, the scores in both groups were about the same.
- Patients treated with galantamine showed a small improvement in behavioral symptoms (NPI scores) that lasted for 6 months before crossing the baseline level and continuing to decline. During that same period, however, the placebo group showed a sharp worsening of symptoms, which leveled off when they began receiving galantamine. After 18 1/2 months, the decline in the NPI scores of the galantamine group was similar to that experienced by the placebo group at 5 months.
Early Prevention = Long-Term Benefits
In summary, galantamine treatment provided long-term (18 1/2 months) benefits, especially in cognitive functions: after significant initial gains, these functions remained above the baseline level for one year before declining further. (Interrupting the treatment appeared to be quite detrimental.) Thus, the clock was stopped, in effect, for a year—a major plus in the struggle to prolong life while maintaining functional capacity.
Such improvement with galantamine is particularly gratifying, because with conventional anti-Alzheimer’s drugs, the best one can usually hope for is to stop losing ground for about 6 months, after which the drugs start to lose their effectiveness, and the decline in functional capacity resumes.
It’s important to realize, of course, that Alzheimer’s disease doesn’t arise from nowhere. Its common precursor is the less serious condition known as mild cognitive impairment (MCI), which usually, but not always, leads to Alzheimer’s. MCI is not to be confused (although that’s not always easy) with the benign memory impairment attributed to normal aging, which afflicts just about everyone if they get old enough. Since memory impairment, especially of verbal memory, is a strong predictor of Alzheimer’s, it pays to be vigilant and to take early preventive action.
A Priceless Gift
What is time worth? What is life worth? No one can answer such questions, but we all recognize the primal urge to prolong life for as long a time as possible, even when the ultimate outcome is a foregone conclusion. How gratifying it is, then, to see that a brain damaged by Alzheimer’s disease can stage a comeback, even if only for a few months to a year, and cling to the capabilities—and memories—that make life so precious. And for that remarkable and unexpected ability, we have galantamine to thank.
- Tariot PN, Solomon PR, Morris JC, Kershaw P, Lilienfeld S, Ding C. A 5-month, randomized, placebo-controlled trial of galantamine in Alzheimer’s disease. Neurology 2000;54:2269-76.
- Raskind MA, Peskind ER, Wessel T, Yuan W, and the Galantamine USA-1 Study Group. Galantamine in AD: a 6-month, randomized, placebo-controlled trial with a 6-month extension. Neurology 2000;54:2261-8.
- Wilcock GK, Lilienfeld S, Gaens E, on behalf of the Galantamine International-1 Study Group. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer’s disease: a multicentre randomised controlled trial. Brit Med J 2000;321:1445-8.
- Olin J, Schneider L. Galantamine for Alzheimer’s disease (Cochrane review). In The Cochrane Library, Issue 2, 2001. Oxford: Update Software.
- Lyketsos CG, Reichman WE, Kershaw P, Zhu Y. Long-term outcomes of galantamine treatment in patients with Alzheimer disease. Am J Geriatr Psychiatry 2004;12(5):473-82.
- Small BJ, Mobly JL, Laukka EJ, Jones S, Backman L. Cognitive deficits in preclinical Alzheimer’s disease. Acta Neurol Scand 2003;107(Suppl 179):29-33
Galantamine provides a heralded dual-mode action for boosting cholinergic function: it inhibits the enzyme acetylcholinesterase, thereby boosting brain levels of acetylcholine, and it modulates the brain's nicotinic receptors so as to maintain their function. 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.
For an added measure of benefit, it is a good idea to take choline, the precursor molecule to acetylcholine, as well as pantothenic acid (vitamin B5), an important cofactor for choline. Thus it is possible to cover all bases in providing the means to enhance the levels and effectiveness of your acetylcholine.
Will Block is the publisher and editorial director of Life Enhancement magazine.