I can speak for the pharmacological end of AD research, since I work for a drug company (organic chemist) doing research on the subject. The field is in its usual ferment. The hypothesis that amyloid protein is the causitive agent is still very much live, with a lot of effort going into finding out what protease enzymes are responsible for making it - this would be a good area for pharmaceutical intervention. Nerve growth factors are also being investigated for the same reason. Recent reports that implicate the Apo-E protein and, in another hypothesis, estrogen levels, are too new to really be judged. The aluminum hypothesis is probably much lower on the list than it used to be, since the high levels of aluminum that were reported originally have been shown to be artifacts. Current Research on New Alzheimer's Therapies I'd divide current research in the industry into three broad classes, palliative and curative:
Tacrine (Cognex) is in the first category, as are all drugs of its type.
The neurotransmitter acetylcholine decreases during AD, and the body normally clears it out with an enzyme called AChE. These drugs are designed to interfere with that enzyme, and thus increase the amount of acetylcholine and its lifetime in the brain. The enzyme is the reason why just giving acetylcholine directly doesn't work, by the way.
The problem is that it's used in many other organs as well, and those may not take well to having excesses around. Also, even in the brain, you're not targeting any specific areas or cells - just anything that responds to acetylcholine, which is a pretty wide target, maybe too wide.
There are a number of compounds out there in testing, though, and that's the only way to find out if any of them will be therapeutically useful. The hope is that some of them will prove to be less toxic than tacrine, so the dosages can be increased. These are definitely the closest to market.
Another way to attack AD via acetylcholine is through the receptors on neurons that respond to it. These are the actual sites on the outer surface of nerve cells that acetylcholine fits into to set off the signal that it's designed to pass on. There are five different receptors in the brain that we know of that could be important for this (the total number of different receptor kinds is huge, and it's getting worse all the time, by the way!) If you could find a drug that activates the type known as m1, or one that blocks the type known as m2, then the amount of acetylcholine should increase. The second has a better chance of having a drug found for it, since it's almost always easier to block a process than to find the right thing to start it off.
The m2 receptor actually is present at the synapse on the "upstream" neuron. When that neuron releases acetylcholine into the synapse, it makes its way to the "downstream" neuron and fits into its m1 site (which is why a synthetic m1-binding compound would be a replacement therapy.)
Meanwhile, some of the acetylcholine binds to the m2 site on the first neuron, which sends a signal to turn off the acetylcholine flow, that there's enough out in the synapse already. If we could block that signal, the neuron would pump more acetylcholine out than normal. And if you're wondering what the m3, m4, and m5 types do - the answer is that no one really knows yet.
Both of those therapies would slow the progression of the disease and help its symptoms. To stop it, we have to know what's causing it in the first place, and the current favorite is the deposition of a protein called beta-amyloid in the brain. It's clipped off of a larger protein called APP, which is used in the brain and many other organs - for what, we don't know, but it's everywhere. But only in the brain, and only in the aged, does it seem to get broken up in a way that releases beta-amyloid. That fragment is very insoluble, and it precipitates around the neurons and kills them off in tangles. (We think that it does that by interfering with calcium concentrations at the neuron surface, but that's unclear).
At any rate, if we could find out what enzyme in the brain is breaking up the APP molecule, we could design a drug to block it, and thus stop the disease. . .if the idea that beta-amyloid is causing it is right. That's still open for debate, too, but many companies are trying this idea out. Interfering with enzymes is a very popular method for designing drugs; we're always ready to roll when we can find a way to go after a disease by that route.
Finally, there's reversal of the damage. This is the most desirable route, and it's also the hardest and the farthest from testing. Most of the time, damage to the central nervous system is permanent - as in stroke or spinal injury. Alzheimer's damage is in the same category.
There are proteins, though, that will cause neurons to resprout and make new connections under the right conditions. But they're too large and unstable to take any other way than injecting directly into the brain, which is just too dangerous - you'd probably do more damage than good that way. It's hoped that if we can find what signals the brain needs to start producing those compounds on its own, that we could stimulate it to start re-connecting neurons to make up for damage.
Frankly, we don't know what those signals are (although there are some interesting possibilities,) and we don't know if the resprouting will actually work like we hope (although some animal models have given hopeful results), and we don't know what harm it might to to even try. But it's certainly worth a shot.
As you can see, we're really handicapped by our lack of knowledge of the brain. Although a tremendous amount has been learned, it's dwarfed by the insanely complicated structure and chemical signaling pathways that turn up every time we look closely. I sometimes wonder if the brain is able to comprehend the brain, if you know what I mean. But this is the most exciting time to be in central nervous system chemistry and biology, ever, because where there's a lot that's unknown, there's a lot to be found.
Derek Lowe Kenilworth, New Jersey
