Pfizer and Eisai picked up some headlines on the news that their Alzheimer's drug, Aricept (donezipil) showed some effectiveness in delaying the onset of Alzheimer's. That used to be my field of work, although I've got no competing interest in that therapeutic area now. I make that disclaimer up front, because I'm not all that impressed by this new study.

Aricept is a cholinesterase inhibitor, part of the first wave of compounds that were brought in as Alzheimer's therapies. Inhibiting cholinesterase increases the amount of a key neurotransmitter (acetylcholine) that hangs around in the synapse, which should, in theory, lead to stronger signaling between neurons. But this is and always has been a brute-force mechanism, real back-of-the-envelope stuff, which I realized even when I used to work on something pretty similar.

We don't understand neurotransmission well enough to be sure that we're doing much good just by turning up synaptic signaling. To add to the problem, the relevant cholinergic neurons are among those being damaged by Alzheimer's itself, so the drug's therapeutic target is slowly disappearing. That's why the cholinesterase inhibitors are recommended for very early stages of Alzheimer's, and are considered useless for late stages of the disease.

And that's why Pfizer went out as early as possible, out to before patients had even shown signs of Alzheimer's at all. It appears that Aricept therapy helped slow the onset of the disease, among those who developed it at all. Problem is, the effect wasn't large, and after three years any benefit had completely disappeared. The placebo-treated Alzheimer's patients were in the same shape as the ones who had been getting Aricept all along. (Note that Aricept has been studied in non-Alzheimer populations before.)

You wouldn't know all this from a quick look at most of the popular press, though, which went with New Breakthrough headlines like "Drug is First to Delay Onslaught of Alzheimer's." (Science, on the other hand, went with "Study Questions Efficacy of Popular Alzheimer's Treatments", which is more like it.) I'm in the same camp, and it's the same one as the editorial from the issue of the New England Journal of Medicine where the study appeared. Aricept, the journal said, "may offer some benefit, but any such benefit is quite limited and apparently transient" Try turning that into something that'll make you sit past the commercial break. . .

So Johnson and Johnson is the latest company to try to broaden their market for a drug and run into cardiovascular side effects. Their Alzheimer's drug Reminyl (galantamine), makes some money, but is hardly a blockbuster. It's a natural product (derived from daffodil bulbs, of all things), and it's a cholinesterase inhibitor, the same mechanism as the two other Alzheimer's drugs on the market. None of them are gigantic sellers, because they don't do all that much for people, especially once they have serious symptoms. But if you could show beneficial effects in the pre-Alzheimer's population, then the potential number of patient could be much larger. I should, in fairness, point out that the potential benefits to the patients could be larger, too: earlier treatment before the disease has had more time to do irreversible damage.

Cholinesterase inhibition is a pretty crude tool to help Alzheimer's, but it's all that we have at the moment. The idea is the turn up the volume of neuronal signals that use acetylcholine as a transmitter molecule, by inhibiting the enzyme that would break it down and sweep it out of the synapse. I don't see an obvious connection between this mechanism and the cardiovascular effects that showed up in J&J's trial.

This is another illustration of the same thing that's bringing down the COX-2 inhibitors. The larger the population that takes your drug, and the more clinical trials you run, the better your chance of finding the side effects. All drugs have side effects, and if you turn over enough rocks you'll see them. But without expanding the patient population, you won't be helping all the people you could help, and you won't be making all the money you could make. It's like walking through a minefield. It's what we do for a living over here. What a business!

The October 29th issue of Science has an interesting article from a team at Stanford on a possible approach for Alzheimer's therapy. The dominant Alzheimer's hypothesis, as everyone will probably have heard, is that the aggregation of amyloid protein into plaques in the brain is the driving force of the disease. There's some well-thought-out dissent from that view, but there's a lot of evidence on its side, too.

So you'd figure that keeping the amyloid from clumping up would be a good way to treat Alzheimer's, and in theory you'd be correct. In practice, though, amyloid is extremely prone to aggregation - you could pick a lot of easier protein-protein interactions to try to disrupt, for sure. And protein-protein targets are tough ones to work on in general, because it's so hard to find a reasonable-sized molecule that can disrupt them. It's been done, in a few well-publicized cases, but it's still a long shot. Proteins are just too big, and in most cases so are the surfaces that they're interacting with.

The Stanford team tried a useful bounce-shot approach. Instead of keeping the amyloid strands off each other directly, they found a molecule that will cause another unrelated protein to stick to them. This damps down the tendency of the amyloid to self-aggregate. The way they did this was, by medicinal chemistry standards, simplicity itself. There's a well-known dye, the exotically named Congo Red, that stains amyloid very powerfully - which must mean that it has a strong molecular interaction with the protein. They took the dye structure and attached a spacer group coming off one end of it, and at the other end they put a synthetic ligand which is known to have high affinity for the FK506 binding protein (FKBP). That one is expressed in just about all cell types, and there are a number of small molecules that are known to bind to it.

The hybrid molecule does just what you'd expect: the Congo Red end of it sticks to amyloid, and the other end sticks to FKBP, which brings the two proteins together. And this does indeed seem to inhibit amyloid's powerful tendency for self-aggregation. And what's more the aggregates that do form appear to be less toxic when cells are exposed to them. It's a fine result, although I'd caution the folks involved not to expect things to make this much sense very often. That stich-em-together technique works sometimes, but it's not a sure thing.

So. . .(and you knew that there was going to be a paragraph like this one coming). . .do we have a drug here? The authors suggest that "Analogs based on (this) model may have potential as therapeutics for Alzheimer's disease." I hate to say it, but I'd be very surprised if that were true. All the work in this paper was done in vitro, and it's a big leap into an animal. For one thing, I'm about ready to eat my own socks if this hybrid compound can cross the blood-brain barrier. Actually, I'm about ready to sit down for a plateful of hosiery if the compound even shows reasonable blood levels after oral dosing.

It's just too huge. Congo Red isn't a particularly small molecule, and by the time you add the linking group and the FKBP ligand end, the hybrid is a real whopper - two or three times the size of a reasonable drug candidate. The dye part of the structure has some very polar sulfonate groups on it, as many dyes do, and they're vital to the amyloid binding. But they're just the sort of thing you want to avoid when you need to get a compound into the brain. No, if this structure came up in a random screen in the drug industry, we'd have to be pretty desperate to use it as a starting point.

Science's commentary on the paper quotes a molecular biologist as saying that this approach shows how ". . .a small drug becomes a large drug that can push away the protein. . ." But that's wrong. You can tell he's from a university, just by that statement. I'm not trying to be offensive about it, but neither Congo Red nor the new hybrid molecule are drugs. Drugs are effective against a disease, and this molecule isn't going to work against Alzheimer's unless it's administered with a drill press. If that's a drug, then I must have single-handedly made a thousand of them. The distance between this thing and a drug is a good illustration of the distance between academia and industry.

To be fair, this general approach could have value against other protein-protein interaction targets. I think that it's worth pursuing. But I'd attack something other than a CNS disease, and I'd pick some other molecule than Congo Red as a starting point.

One of the comments in my post on animal models prompts me to write a bit more on mutations. I stated that the mutant animal models that we use all have something wrong with them, but I didn't mean to imply that all mutations will do that. There are plenty of so-called "silent" mutations out there, single amino-acid changes in large proteins that basically make no difference. If you switch, say, valine for isoleucine, most of the time it's not going to hurt much (or help much.) (The reason our mutant animals have something wrong with them is that we're trying to mimic a diseased human; if they weren't defective, we wouldn't be interested.)

Billions of years of evolution have honed things down pretty well. If a protein gets altered, it's a lot easier to have a sudden loss of function than it is to have a sudden gain. It's like popping your hood and throwing rocks at your car engine - you have a better chance of damaging the thing than you have of whacking it in a way that increases your gas mileage.

I wrote about a particularly vivid example of this a couple of years ago on my old Lagniappe site. (That material seems to be succumbing to bit-rot when I try to pull it out via Google, so I'm going to rescue some of it every so often.) Here's a slightly reworked version of what I had to say about a famous Alzheimer's mutation:

One of the things that gives me the willies about biochemistry is the nonlinearity. If anyone were to ever come up with a set of equations to model all the ins and outs ofa living organism, there would be all these terms - way out in the boonies of the expression - with things to the eighth and tenth powers in them.

Of course, the coefficients in front of those terms would usually be zero, or close to it, so you'd hardly know they were out there. But if anything tips over and gives a little weight to that part of the equation. . .suddenly something unexpected wakes up, and a buried biological effect comes roaring to life out of nowhere.

Here's the real-world example that got me thinking in that direction. When I used to work on Alzheimer's disease, I first learned the canonical Amyloid Hypothesis of the disease. Briefly put, at autopsy, the brains of Alzheimer's patients always show plaques of precipitated protein, surrounded by dying neurons. It's always the same protein, a 42-amino-acid number called beta-amyloid. A good deal of work went into finding out where it came from, namely, from a much larger protein (751 amino acids) called APP. That stands for "amyloid precursor protein," in case you thought that acronym was going to tell you something useful

The ever-tempting hypothesis has been that an abnormal accumulation of beta-amyloid is the cause of Alzheimer's. This isn't the time to get into the competing hypotheses, but amyloid has always led the pack, notwithstanding a vocal group of detractors who've claimed that Alzheimer's gives you amyloid deposits, not the other way around. (Note from 2004: I wrote recently about developments in the amyloid field here and here.)

So what's APP, and what's it good for? It took all of the 1990s to answer that one, and the answers are still coming in. It's found all over the place, and seems to have a role in cellular (and nuclear) signaling. Normally, it's cleaved to give smaller protein fragments other than the 42-mer that causes all the trouble.

One of the stronger arguments for amyloid as an Alzheimer's cause came from the so-called "Dutch mutation," which is what got me to thinking. As was worked out in 1990, there's a family in Holland with a slightly different version of APP. One of the 751 amino acids is changed - where the rest of the world has glutamic acid, they have glutamine - almost the same size and shape, but lacking the acidic side chain.

So. . .there's one amino acid out of 751 that's been altered. And that's in one protein out of. . .how many? A few hundred thousand seems like the right order of magnitude for the proteome, maybe more. And what happens if you kick over that particular grain of sand on the beach? Well, what happens is, you die - with rampaging early-onset Alzheimer's (and a high likelihood of cerebral hemorrhage) before you're well into your 40s.

As it happens, that amino acid is right in the section of the protein that becomes beta-amyloid. Altering it makes it much easier for proteases to come and break the amide bond in the protein backbone, so you start accumulating beta-amyloid plaques early. Much too early. Bad luck - the change of just a few atoms - snowballs into metabolic disaster. Since then, many other mutations have been found in APP, and many of them are bad news for similar reasons.

But it's not like every amino acid substitution in some random protein causes death, of course. There are any number of silent mutations, and plenty that are relatively benign. Most of the time, those high-exponent terms out there in the mathematics sleep on undisturbed. And it's better that way.

After a (reasonably) refreshing holiday break, Lagniappe is back. Thanks to everyone who kept doggedly hitting this site during the last few days - I admire your persistance.

I notice from my site's counter that I get a small but steady flow of Google hits for various miracle cures. I said some nasty things about the Budwig flaxseed-oil diet a while back, for example, and I still get Googled for that one. For those visitors, here's a post that (with any luck) will show up for a long time to come.

To put it in one sentence, distrust simple cures for complex diseases. Cancer is a complex disease, so are arthritis, MS, Alzheimer's and diabetes. What's a simple disease? An infectious one: there's a proximate cause, and a path to cure it. Get rid of the bacteria, and your septicemia goes with them. Clear out the parasites, and no more malaria. (You'll note that we don't have a universal malaria cure yet, which should say something about how hard even the simpler diseases are.)

The really tough ones, though, are all things that originate from some misfiring of the body's own systems. It's true that there are single-gene diseases, which would be simple to treat if we only knew how to get gene therapy to work. Most of them are rarities, diagnostic zebras that many physicians will never see. The ones that every physician sees are multifactorial and very hard to deal with.

I've spent a lot of time on this site talking about autism recently, and there's a common factor. I believe that many diseases only look like single conditions, which turn into dozens of other diseases on closer inspection. There's no such disease as "cancer," for example. Cancer is the name we sloppily apply to the end result of dozens, hundreds of metabolic or genetic defects and breakdowns, all of which end up as vaguely similar cell-differentiation diseases. It wouldn't surprise me if Alzheimer's ends up as something that can be caused several different ways, all of which end up in the same alternate low-energy state for the brain's metabolic order. (I speculated on this back in the first month of this blog's existence.)

And autism, too, could well be the name we're giving to several different diseases, distinguished by their time course, onset, and severity, caused by all sorts of intricate interplay - the wrong chord played on the instrument at just the wrong time.

You can, at times, find single factors that lead into these diseases - a compound called benzidine leads to bladder cancer, for example, although not in every person exposed, and at unpredictable exposures over unpredictable times. But that doesn't mean that everyone who has bladder cancer has been exposed to benzidine - not many people ever are these days. And stomach cancer, for example, has nothing to do with benzidine at all. Even the simple cases aren't too simple.

Remember the power line scare? How those electromagnetic fields from high-tension lines were messing up everyone's lives? You could see stories about how power-line exposure had been linked to brain cancer, to kidney cancer, to skin cancer. The problem was, one study would show a barely-there tenuous link to brain cancer - but not to anything else. Another would show the same wispy possible connection to kidney cancer - but not to anything else. And so on - after looking over all the data, the best conclusion was that this was all statistical noise. Beware statistical noise - that's another long-running theme around here.

Epidemiology hasn't been a simple field since the days of yellow fever, if it even was then. And medicine hasn't been a simple one since the first days that ever counted. As time goes on, we're clearing out more and more of the easy stuff. The really hard stuff is what's left, and it's going to be resistant to simple fixes.

The Alzheimer's vaccine idea that I've covered every so often is back in the news. Two studies coming out in Nature Medicine give it a boost. One shows that the ill-fated Elan clinical trial (which came to a screeching halt when some patients developed brain inflammation) actually did lead to antibody production against the beta-amyloid protein. The antibodies recognized various types of amyloid deposits, and crossed into the brain. (That last part is what has amazed everyone since the first animal results - antibodies aren't supposed to be big players across the blood-brain barrier.)

The other paper reports that a very similar response in rodents can be achieved using a much smaller variant of the amyloid protein. That should lower the chance of inflammatory side-effects considerably, and gives new hope to human studies. This is looking like one of the crazy ideas that just might work - stipulating, for the moment, that amyloid really is the cause of Alzheimer's. . .

One of the things that gives me the willies about biochemistry is the nonlinearity. If anyone were to ever come up with a set of equations to model all the ins and outs ofa living organism, there would be all these terms - way out in the boonies of the expression - with things to the eighth and tenth powers in them.

Of course, the coefficients in front of those terms would usually be zero, or close to it, so you'd hardly know they were out there. But if anything tips over and gives a little weight to that part of the equation. . .suddenly something unexpected wakes up, and a buried biological effect comes roaring to life out of nowhere.

Here's the real-world example that got me thinking in that direction. When I used to work on Alzheimer's disease, I first learned the canonical Amyloid Hypothesis of the disease. Briefly put, at autopsy, the brains of Alzheimer's patients always show plaques of precipitated protein, surrounded by dying neurons. It's always the same protein, a 42-amino-acid number called beta-amyloid. A good deal of work went into finding out where it came from, namely, from a much larger protein (751 amino acids) called APP. That stands for "amyloid precursor protein," in case you thought that acronym was going to tell you something useful

The ever-tempting hypothesis has been that an abnormal accumulation of beta-amyloid is the cause of Alzheimer's. This isn't the time to get into the competing hypotheses, but amyloid has always led the pack, notwithstanding a vocal group of detractors who've claimed that Alzheimer's gives you amyloid deposits, not the other way around.

So what's APP, and what's it good for? It took all of the 1990s to answer that one, and the answers are still coming in. It's found all over the place, and seems to have a role in cellular (and nuclear) signaling. Normally, it's cleaved to give smaller protein fragments other than the 42-mer that causes all the trouble.

(To get away from my main point, whether beta-amyloid has any normal biochemical use is a question that can still start some major arguments. Vast amounts of money and time (a very tiny percentage of it mine) have gone into trying to find the proteases that clip it out of APP, and to finding small drug-like molecules to inhibit them. We're finally to the point of having those, and the amyloid hypothesis is getting the acid test in the clinic. That'll all be a topic for another day.)

At any rate, one of the stronger arguments for amyloid as an Alzheimer's cause came from the so-called "Dutch mutation," which is what got me to thinking. As was worked out in 1990, there's a family in Holland with a slightly different version of APP. One of the 751 amino acids is changed - where the rest of the world has glutamic acid, they have glutamine - almost the same size and shape, but lacking the acidic side chain.

So. . .there's one amino acid out of 751 that's been altered. And that's in one protein out of. . .how many? A few hundred thousand seems like the right order of magnitude for the proteome, maybe more. And what happens if you kick over that particular grain of sand on the beach? Wll, what happens is, you die - with rampaging early-onset Alzheimer's (and a high likelihood of cerebral hemorrhage) before you're well into your 40s.

As it happens, that amino acid is right in the section of the protein that becomes beta-amyloid. Altering it makes it much easier for proteases to come and break the amide bond in the protein backbone, so you start accumulating beta-amyloid plaques early. Much too early. Bad luck - the change of just a few atoms - snowballs into metabolic disaster. Since then, a href="http://web.utk.edu/~saydin/omimab.html">many other mutations have been found in APP, and many of them are bad news for similar reasons.

But it's not like every amino acid substitution in some random protein causes death, of course. There are any number of silent mutations, and plenty that are relatively benign. Most of the time, those high-exponent terms out there in the mathematics sleep on undisturbed. And it's better that way.

There's a report today that an Alzheimer's medication seems to help memory function even in people who don't have the disease. As reported in Neurology, pilots using a flight simulator performed better when repeating tasks learned while taking Pfizer's drug donepezil (Aricept - it's actually an Eisai drug that Pfizer licensed.)

Before anyone gets too excited, the changes, although statistically meaningful, were small. A quote in the NY Times science section today compared the size of the enhancement to that of the deficit imposed by, say, a hangover. For some people's hangovers that's probably an impressive yardstick, but it was meant to suggest a modest improvement. Still, there's an interesting concept here, and it's been much on the minds of researchers over the years.

Some background: Aricept is a cholinesterase inhibitor, which basically replaced the first such compound on the market, Tacrine (which had sporadically nasty liver toxicity.) As far as I know, it has most of the market for that mechanism. Other companies (such as Bayer) have tried to bring compounds to market, but getting them right can be difficult. After all, a good example of a truly effective, fast-acting cholinesterase inhibitor is nerve gas. You want to back away from that kind of activity for Alzheimer's patients, of course, but side effects are still possible.

And even if the compound is clean, there's only so much a cholinesterase inhibitor can do for someone with Alzheimer's. At best, you can hope to slow the progression of the disease a bit, and response rates vary. Some patients probably show improved quality-of-life, but others are likely wasting their time and money. The whole basis of cholinergic therapy for Alzheimer's (a field I've worked in,) is fairly crude: jacking up the levels of the neurotransmitter acetylcholine across the board. Admittedly, this idea can work for other neurotransmitters (dopamine in Parkinson's disease, or serotonin in depression.) But (just as in the Parkinson's case) it doesn't address the underlying disease; it just tries to ameliorate the symptoms while things get inexorably worse.

But what about people who don't have Alzheimer's? As mentioned above, I can tell you that that question has crossed the mind of everyone working in the memory-enhancement field. What if your drug makes diseased brains more normal, and normal brains. . .better than that? The FDA hasn't dealt much with such issues, understandably, and I can't think of a company that's had the nerve to ask them. But while the market for an effective Alzheimer's drug would be large, the market for a safe memory drug for the general population could be gigantic. The benefits could be similarly huge.

The closest analogy I can think of is the obesity market. Right now, there's no good drug therapy for obesity, period, although people spend billions of dollars trying to say otherwise. Most people's idea of a good obesity drug would be the Magic Pizza Pill - you know, the one you take, and then you can eat all the pizza you want. Don't hold your breath for it; I don't think it's possible. But even a reasonably effective obesity drug would be a huge seller.

And the unspoken assumption about any such drug is that a significant number of the people taking it would not necessarily be all that obese. There are certainly enough obese people to make for a successful drug, and more coming all the time, but there are plenty of folks who would just want to look a little better. Nothing wrong with that, since even modest weight loss is very likely a good thing. But the regulatory assumption is that weight-loss drugs would go primarily to the morbidly obese, whose lives are in more immediate danger. That's not nearly as large a potential market (although at the rate we're going, it could end up being one.)

Companies working on memory-enhancing drugs have had the same thoughts, and done the same math. That said, many of the current therapies being tried for Alzheimer's aren't in this category, since they're more specifically aimed at what seem to be the disease processes. Even among those groups working on memory in general, the odds of dramatically improving function are low. You'd figure that the system is fairly well optimized by now. But what if you did find one? How many people would line up for it? It would be an off-label indication with a vengeance.

I doubt if I would take it myself, not until plenty of others had done so for at least a few years. I'm very nervous and twitchy about CNS medications in general (probably from having worked in the field, as I mentioned!) I have no desire to mess with my brain chemistry unless absolutely necessary.

I'd like to take the time to sympathize with Elan Pharmaceuticals over what's happened to their Alzheimer's trial. They had the initiative (and the nerve) to pick up and run with an unusual discovery: that a protein that precipitates in the brains of Alzheimer's patients, beta-amyloid, can be attacked by an immune response.

I'm not going to take sides in the "does amyloid cause Alzheimer's, or does Alzheimer's give you amyloid" controversy. Most money is on the first choice, but there's a vocal minority for the second that makes some good points. At any rate, the idea of going after amyloid deposits by raising antibodies to them was pretty gutsy.

In general, you want to think twice about raising an immune response to one of your own proteins. It's like the old rule of black magic - don't call up anything that you don't know how to send back down. It seems, though, that amyloid, weird and insoluble stuff that it is, looks useless and foreign enough that it can be treated as an invader.

The brain is also considered an immune-privileged organ. You wouldn't have high hopes for a vaccine approach to work there. But they actually cleared amyloid deposits from the brains of rodents (in a special strain bred to have amyloid problems.)

Elan took this into human trials as fast as they could. Unfortunately, they've run into what some feared might be the downfall of the whole approach. Several patients are showing signs of central nervous system inflammation. The immune response appears to have gotten out of hand.

There may be a way to fix this, but it'll be a while before anyone is able to try this approach again. A lot of ground work will have to be done first. It's a pity, because this had the potential to be a home run against a disease that's consumed minds, lives, and a vast amount of research time, money, and talent.

That neuroscience business came up, I guess, because I have a minor background in it. I broke into the drug business doing work on schizophrenia, and followed that with several years on Alzheimer's.

If some of the people in the field read this - well, don't take it the wrong way - but I'd almost as soon have a job breaking concrete with my nose. The central nervous system is a very, very hard area to work in. That's partly because brain function is hideously complex: it's an interesting question whether a human brain even has enough ability to comprehend its own workings. But it's partly because a key part of the drug-testing cascade is often missing.

That's animal testing. (And it really is a key part - eventually I'll get into it with the anti-in vivopeople, and I'll argue that position as long as it takes.) The problem with many central nervous system targets is that the animal models either don't exist, or (even worse) exist but are untrustworthy. That last situation is a killer: the models persist because there is a constituency that believe in their relevance. You'll be running into those folks over and over if you try to do without, and they're going to refuse to believe in your drug candidate unless it's been through the wildebeest swim maze, the platypus tail flick assay, whatever.

The models are so hard because you're often trying to affect behavior that is unique to humans - like remembering phone numbers. Whether a rat can remember not to run into the electrified part of the cage is of doubtful relevance. I think that there are many kinds of memory storage, and I don't believe that rats partake of the kinds that we're most worried about. It's true that there must be common molecular mechanisms for all types of memory (at some level) but messing with those processes indiscriminately (the only way we know how, in many cases) is a recipe for trouble. Let's not even get started on the topic of animal models for schizophrenia.

There's been a lot of progress in Alzheimer's the last two or three years. I enjoy reading about it, and I wish everyone working there all the luck in the world. I may need your compounds some day, guys, so keep banging away. But I'm glad that I'm not having to bang away with you.