Galantamine Works Even Better than Was Thought

Galantamine Helps in “Advanced Moderate” Alzheimer’s

Galantamine Works Even 
Better than Was Thought
In which you, the reader, discover a clever way to do some needed Alzheimer’s research
By Will Block

n this article, dear Reader, you’re going to be a medical researcher, with an M.D. or Ph.D. under your belt (maybe even both, as is true of some overachievers), and a white lab coat that says you mean business. You’re going to solve a tricky problem in Alzheimer’s research, in which you have a keen professional interest—as do thousands of your colleagues around the world. Many of them have contributed to the huge body of medical literature on the subject, in fields such as neurophysiology, biochemistry, molecular biology, pharmacology, gerontology, and pathology—in all of which, of course, you are well versed, even if you’re not an expert in all of them.

Most such research is conducted in laboratory experiments or on lab animals, such as mice—including mice in which an Alzheimer’s-like condition is artificially induced through genetic engineering. (See Galantamine Rescues Damaged Brain Cells in last month’s issue of Life Enhancement—the one with the cute little mouse on the cover.)

Some of your colleagues, of course, have conducted clinical trials on human Alzheimer’s patients to evaluate the efficacy and safety of various drugs or natural remedies. Ultimately, it’s in clinical trials where the rubber meets the road, so to speak, because all the hard-science research is useless (albeit mighty interesting to scientists) if it doesn’t lead to actual therapies that work. And some therapies do work—not as well as anyone would like, of course, but well enough to offer hope and encouragement for millions of Alzheimer’s victims and their caregivers.

Galantamine Is Effective in Mild to Moderate Alzheimer’s

As an expert in the field, you have noticed three things that pique your interest:

  1. There is strong evidence from clinical trials showing that the best available treatment for Alzheimer’s disease is a natural compound called galantamine, which is derived from several kinds of flowers.
  2. Five of the pivotal galantamine studies—the most thorough ones, which clinched the case for its efficacy—were done using patients whose conditions were described as “mild to moderate”—no severe cases were included.1–5
  3. Two of the pivotal studies showed that galantamine’s efficacy remained strong for at least 12 months (the duration of those studies).3,5 By contrast, studies with other anti-Alzheimer’s agents have typically shown declining efficacy after about 6 months, apparently because of increasing tolerance (i.e., resistance) to the drugs.

But What About More Serious Cases?

Naturally, you’re curious: if galantamine has both substantial and sustained benefits in mild to moderate cases of the disease—as it indisputably does—what about more serious cases? Would it still work as well, and for as long, in those cases—or not so well, or perhaps not at all? Your inquiring mind wants to know, and your compassionate nature naturally wants to provide treatment for the many patients in the more advanced stages of the disease who are currently not getting it.

The main reason these patients are not getting treatment is because of a lack of demonstrated efficacy of galantamine (as well as other agents) at the more advanced levels of the disease. That’s because the protocols in the pivotal studies—and in almost all the studies, for that matter—excluded such patients from participation. (This was done for sound reasons—and in any given study, you have to draw the line somewhere.)

Finding Out Won’t Be Easy

Well, you think, it’s clearly time to take the next big step in demonstrating galantamine’s efficacy. So you write a proposal, get a grant, set up a 12-month clinical trial using patients who are much farther down the one-way road to dementia than the previous ones, and find out whether galantamine is effective for them too.

If only it were that easy. A full-scale clinical trial is a complicated and expensive undertaking that’s extremely difficult to do well (and most of them, frankly, are not done very well, for various reasons). Let’s say your proposal is first-rate (of course!), but the funding just isn’t available for a full-scale trial with a sufficiently large group of patients for a 12-month period, or you lack the appropriate facilities, or something else gets in the way. What do you do?

You Can Mine New Results from Earlier Studies

Why, you get clever, of course, and start thinking outside the box. If you can’t set up your own trial, perhaps there’s a way to extract some useful information from the data in the two long-term galantamine trials that their authors overlooked. The trouble is, though, that those trials included only mild to moderate cases of Alzheimer’s disease, as we’ve already seen. And no matter how hard you try, you can’t extract information on severe (late-stage) cases of the disease from studies that didn’t include such cases, any more than you can get mustard out of a ketchup bottle by squeezing it extra hard.

What you can do, though, is look at subsets of the previous data that focus on the high end of the range of severity of cases that were included—in other words, the cases that could be classified as “advanced moderate,” which is just shy of being classified as severe. After all, if the studies included the full range of moderate as well as mild cases, then some of those moderate cases had to be at the high (advanced) end.

Those cases are the ones you want to take a closer look at, because until you do, you can’t know for sure whether or not they benefited from galantamine as much (or at all) as the milder cases. It’s possible, of course, that they didn’t. And if that were true, then their mere presence within the mild to moderate group of patients would have skewed the results somewhat by reducing the average benefits observed for the entire group.

Not a Giant Leap, but . . .

Thus, finding out about all this (assuming, again, that it’s all true—and we don’t know that it is) would tell you two things: (1) the more seriously afflicted patients in the overall group had received less (or even no) benefit than had been thought, based on the original data analysis, and (2) the less seriously afflicted patients in the overall group had received more benefit than had been thought. Those are two things well worth knowing if you want to advance our understanding of galantamine in Alzheimer’s therapy. Which, of course, you do.

Naturally, you may be a bit disappointed not to be able to take the “giant leap for mankind” that you had envisioned: investigating the benefits of galantamine in the more severe, late-stage cases of Alzheimer’s disease. But the “one small step for a man” that you are going to take will be in the right direction: it will be useful and will help pave the way for other researchers down the line.

You’ve Stepped into a Pickle

Now, how do you go about identifying these “advanced moderate” cases of Alzheimer’s disease from among all the patients included in the two long-term galantamine studies? Simple: you apply a data filter to the original (pooled) data, one that’s set to select those patients with baseline MMSE scores of 14 or less; and then, because you’re a thorough researcher, you apply another data filter that’s set to select those with baseline ADAS-cog scores of more than 30.* This gives you two defined subsets of the original (pooled) patient groups. Although these subsets are not identical, they do have some overlap and can be regarded as similar in terms of the progress of the disease, namely, the advanced moderate stage.

*Baseline means measured at the outset of the study, before treatment begins. And for an explanation of the terms MMSE and ADAS-cog, see the sidebar, “How Are Alzheimer’s Patients Classified?”

How Are Alzheimer’s Patients Classified?

The term “advanced moderate” sounds a bit vague, doesn’t it? How can one make such a judgment—and where does one draw the line—when evaluating things as subjective and multifaceted as cognitive function, behavioral characteristics, and performance in the activities of daily living? Well, one does the best one can, using batteries of standardized tests that have been designed and refined over the years to give numerical scores for just that purpose.

The research described in the accompanying article made use of two such tests for classifying the condition of Alzheimer’s patients. One is the Mini Mental State Examination (MMSE), on which a score of 14 or less qualifies as advanced moderate (the lower the score, the worse the condition). The other test is the Alzheimer’s Disease Assessment Scale, cognitive subsection (ADAS-cog), on which a score of more than 30 qualifies as advanced moderate (the higher the score, the worse the condition).

Although these two tests assess similar patient characteristics, they are different enough that an “advanced moderate” classification in one will not necessarily be produced by the other. Nonetheless, their results are likely to be similar and will probably overlap to a significant degree in any group of patients.

Well, the rest should be easy, right? Just look at the data on galantamine’s benefits for those two subsets of patients, and bingo, you’ll have your answer. Alas, however, that won’t work, because a certain feature of the two long-term galantamine studies represents a stumbling block: they were placebo-controlled for only 6 months, not 12 months. But you’re interested in extracting information from the 12-month results, because they’re much more significant, and without placebo-controlled data, you can’t do it! Before we see how you’re going to get out of this pickle, let’s recap those long-term studies. Go to the sidebar, “With Galantamine, the Earlier the Better.”

With Galantamine, the Earlier the Better

Here’s what happened in those two long-term galantamine studies: the protocols were placebo-controlled (and double-blinded) for only 6 months, because it was considered ethically questionable to continue giving half the patients a placebo for longer than that, when they could be given something—galantamine—that would actually help them. With Alzheimer’s, there can be significant deterioration in 6 months’ time—and, of course, twice that deterioration (or more, because the decline tends to accelerate) in 12 months’ time. What the researchers did, therefore, was to convert the protocol to “open label” at the 6-month point, meaning that for the next 6 months, all the patients received galantamine, and none received placebo.

The results were most gratifying: after 12 months, all the patients had improved, but those who received galantamine from the outset had improved more than those who started receiving it only after 6 months on placebo. The patients in the latter group, when they did start receiving galantamine, improved at a similar rate to that of the former group, but they couldn’t catch up because they were starting from a lower level, i.e., after their condition had declined for 6 months.

Nonetheless, the fact that these patients did improve at about the same rate as the others was very significant, because it showed that the 6-month delay had not diminished galantamine’s ability to help them. One way to think about that is: It’s never too late to start. A better way is: The earlier the better.*

*The importance of starting early is underscored by the fact that the common, age-related condition known as mild cognitive impairment (MCI) is a major risk factor for Alzheimer’s disease and vascular dementia. It can be thought of as a probable, though not guaranteed, precursor condition. Although clinical evidence that galantamine can halt or even reverse MCI does not yet exist (but a major international study is in the works), it seems likely that this will prove to be true. (See Galantamine May Help with Mild Cognitive Impairment in Life Enhancement, February 2003.)

You Hit on a Clever Idea

OK, now back to that pickle you’re in. You want to track the progress of the advanced moderate patients as a separate group for 12 months, but you don’t have a 12-month placebo group for comparison—and that stops you in your tracks. But not for long, because you’re a smart cookie. Having kept up with the literature, you recall that two studies were conducted recently on the use of a drug called sabeluzole in mild to moderate cases of Alzheimer’s disease, with outcome measures similar to those of the two long-term galantamine studies.6,7 The patients in the sabeluzole studies had similar inclusion and exclusion criteria, baseline characteristics, and demographics to those in the galantamine studies. And guess what? They were placebo-controlled for 12 months!

Goodbye, pickle! Seizing on this stroke of luck, you now apply those same data filters to the placebo groups in the sabeluzole studies so as to identify the advanced moderate cases of Alzheimer’s disease, and you use those patients as your controls for the 12-month data on the advanced moderate cases in the two long-term galantamine studies. Isn’t that clever? Uh . . . isn’t that cheating? Well, yes, sort of, except that the data for the placebo group in the galantamine studies fit closely at month 6 with those of the placebo group in the sabeluzole studies, thus validating the whole idea. Besides, you are, of course, going to be up front and explain all this in the paper you’ll write when the study is complete and you have all your results.

Uh-oh. This may be the time to let you in on some bad news: you’ve been scooped! Inspired by the way you’ve thought this whole thing through, a team of researchers from Spain, Israel, Germany, the United States, and Belgium has already gone ahead and done it.8 Dang!

Galantamine Protects Cognitive Abilities

Anyway, here’s what they found: after 12 months on galantamine (24 mg/day), the patients with advanced moderate Alzheimer’s disease in the two long-term studies had done much better, based on their ADAS-cog scores, than the control patients in the sabeluzole studies. Of the subset of galantamine-treated patients who had initially been selected based on their ADAS-cog scores (69 patients, average age 74), 51% maintained or improved their ADAS-cog scores over baseline, compared with only 13% of the controls.

And of the subset of galantamine-treated patients who had initially been selected based on their MMSE scores (26 patients, average age 73), 48% maintained or improved their ADAS-cog scores over baseline, compared with only 4% of the controls. In both subsets, the treatment difference (galantamine vs. placebo) amounted to about 10 points on the ADAS-cog scale after 12 months.

Galantamine Protects Functional Abilities

The patients were also evaluated for functional ability, using a test called Disability Assessment for Dementia (DAD). After 12 months on galantamine, the subset of patients who had initially been selected based on their ADAS-cog scores had declined in functional ability by 6.3 points (the overall average) on the DAD scale, compared with a decline by 20.3 points in the control group—a difference of 14 points. Not all the patients declined, however: 39% of the galantamine-treated group maintained or improved their DAD scores over baseline, compared with 12% of the control group.

For the subset of patients who had initially been selected based on their MMSE scores, the results were similar, though not as impressive: the DAD scores of the galantamine-treated group declined by 9.3 points, on average, vs. 14.5 points for the control group, and 38% of the galantamine-treated group maintained or improved their DAD scores over baseline, compared with 17% of the control group. Owing to the relatively small numbers of patients in this category, however, these results turned out not to be statistically significant when the mathematical analysis was done.

Galantamine Scores Big—Congratulations!

Thus, the efficacy of galantamine in this analysis was confirmed, just as the authors surely hoped it would be. In terms of safety, the results were also positive: galantamine was well tolerated by the patients with advanced moderate Alzheimer’s disease (AD). The majority of adverse events reported were of mild to moderate severity and were predominantly gastrointestinal in nature.

The authors stated, in conclusion:

These data suggest that galantamine is beneficial and well tolerated in patients with “advanced moderate” AD and that benefits are maintained for at least 12 months. . . . The efficacy of galantamine observed in these patients with “advanced moderate” AD is at least as great as that observed in patients with mild-to-moderate disease . . . Galantamine offers consistent, sustained efficacy, regardless of baseline disease severity. . . . We conclude that patients with AD may continue to experience efficacy benefits of clinical value from maintained, long-term galantamine treatment, even into more advanced disease.

Just think—those could have been your words (we can pretend they were). In any case, the important thing is to take the message to heart and realize that galantamine is a safe and effective way to help cope with Alzheimer’s disease, even if you’re starting late. Now that was a research result worth finding. Well done!


  1. Rockwood K, Mintzer J, Truyen L, Wessel T, Wilkinson D, on behalf of the Galantamine International-2 Study Group. Effects of a flexible galantamine dose in Alzheimer’s disease: a randomized, controlled trial. J Neurol Neurosurg Psychiatry 2001;71:589-95.
  2. 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: the Galantamine USA-10 Study Group. Neurology 2000;54:2269-76.
  3. Raskind MA, Peskind ER, Wessel T, Yuan W, on behalf of 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.
  4. 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;321:1445-9.
  5. Wessel T, Gaens E. The long-term cognitive benefits of galantamine treatment in patients with Alzheimer’s disease (poster). 125th Annual Meeting of the American Neurological Association, Boston, October 2000.
  6. Feldman H, Sauter A, Donald A, Gelinas I, Gauthier S, Torfs K, Parys W, Mehnert A. The Disability Assessment for Dementia scale: a 12-month study of functional ability in mild to moderate severity Alzheimer disease. Alzheimer Dis Assoc Disord 2001;15:89-95.
  7. Torfs K, Feldman H. 12-Month decline in cognitive and daily function in patients with mild-to-moderate Alzheimer’s disease: two randomized, placebo-controlled studies (poster). 7th International World Alzheimer Congress, Washington, July 2000.
  8. Blesa R, Davidson M, Kurz A, Reichman W, van Baelen B, Schwalen S. Galantamine provides sustained benefits in patients with “advanced moderate” Alzheimer’s disease for at least 12 months. Dement Geriatr Cogn Disord 2003;15:79-87.

Dual-Action Galantamine

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.  

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