When a lot of remedies are suggested for a disease, that means it can’t be cured.
—ANTON CHEKHOV
BECAUSE THERE’S NO SINGLE, UNIFIED THEORY OF ALZHEIMER’S, teams across the world are working on different bits of it, hoping that their approach will prove to be the key that unlocks the disease. Rather like the Indian fable about the six blind men trying to identify an elephant, some research programs deal with the trunk, some with the tail, some with the leg and others with the ears, some with the torso and others with the tusks, and all have different ideas about what it is they’re identifying. It’s a race, not just because cracking Alzheimer’s this year could save hundreds of millions of people in years to come (it’s a prestigious race) but also because the saving of hundreds of millions of people will involve billions of packets of drugs (it’s also a profitable race). There are fortunes to be made here, beyond the dreams of avarice. The latest estimate online put the dementia drugs market at $37 billion, and that was several years out of date, and is, of course, the pre-breakthrough figure, should the breakthrough ever come. Though it’s possible—some scientists say probable—that Alzheimer’s will never be cured as such, but will be managed with better drugs that keep it at bay, rather like HIV is managed today.
As far as causes of Alzheimer’s go, there are two main camps. One of them, what you might call the plaque orthodoxy, is much bigger and better funded than the other. The plaque orthodoxy says that the formation of plaques is the key process. The other camp, the tau heresy, begs to differ. It suggests that plaque is a red herring and that the answer lies in the tangles, the crumpling and snagging of the ladder rungs in the microtubules, the neuron’s internal communication lines. Work by the tau camp has focused on the adherence of surplus phosphorous molecules onto the tau protein, arguing this is the key process of Alzheimer’s, most probably caused by a genetic switch that could be turned off.
The plaque orthodoxy looks for ways to defuse the beta-amyloid crisis that seems to take place in the brain of sufferers, creating characteristic aggregations between neurons, clogging the neural glue with what look like suspect moles, crusty rounded lumps of something unevenly brownish. Bits of the cells that produce the neurotransmitter acetylcholine break down and become part of the plaque blobs. The plaque orthodoxy, which has been in place now for over twenty years, sees tangles as mysteriously secondary. Some tau heretics have a stiff rebuttal to this: Plaques, they say, are not only a red herring, but might be heroes rather than villains. Plaque, they say, is a sign of the brain trying to protect itself from something (the something that causes the tau to mangle). Plaque, they point out, has been seen in quantity in other instances of brain damage. Alzheimer himself was a tau man.
Don’t go away with the impression that this is a gentlemanly dispute (though it’s true that gentlemanly disputes have been taken into the woods at dawn with pistols). Pistols at dawn is more like it. Pro-tau scientists have had enormous trouble getting research grants or getting their results published in medical journals. The plaque orthodoxy has become quite medieval in its tolerance of heretics. So it’s heartening to see that the latest wonder drug, Rember, is a tau-directed one. Perhaps the orthodoxy is being challenged now. I hope so. I hope the tau-research-blocking drug companies have the good grace to look a little sheepish.
The question is, what’s really behind the mechanism, whether beta-amyloid or tau? What’s making beta-amyloid run wildly out of hand; what’s going on with the tau-tangling phosphorous? Presently, there are two answers: (a) genetic and (b) environmental. It’s conventional to ascribe the root causes of Alzheimer’s to a combination of both. A genetic predisposition and an environmental trigger: that’s mainstream science’s current best guess.
There are those inclined to lay the blame entirely on environment. Those who insist that Alzheimer’s, though not a new condition, is essentially a modern condition, a zeitgeist condition, the defining twenty-first-century disease, also tend to point the finger at multiple pollution. And once pollution is mentioned, a whole underworld of subgroups comes to light. In the United States, there’s been a widespread scare about amalgam fillings in teeth, and the resultant potential for mercury poisoning. Another points the finger at aluminum and other metals in the drinking water; yet another claims it can show evidence that pesticide poisoning in food is to blame. Manganese is spoken of suspiciously. These lines of inquiry may get somewhere or nowhere.
Two other theories doing the rounds:
1. That Alzheimer’s is a prion disease. Prions are peculiar things, infectious proteins whose molecules nudge up to healthy cells and corrupt them. The best known prion disease is called variant CJD, or the human form of mad cow disease. In research, transgenic (genetically modified) mice were given Alzheimer’s by being injected with autopsied brain material. Thus Alzheimer’s was shown to be infectious, though only in this rather specialized and perverse manner.
2. That Alzheimer’s is caused by a virus. Hepatitis C has been mentioned. There has been more convincing talk of herpes simplex, which infects a good many of the world’s population in a dormant state and can be activated by illness, stress, or inflammation.
IN TERMS OF treatment, immunization may be the way forward, certainly in the plaque camp. This idea was scorned when first suggested, but has been piloted with some success. The idea is that it works rather like the polio vaccine: The body attacks the injected beta-amyloid and with any luck also sweeps up the plaques in the brain (though whether this is fundamentally a good idea remains moot). Tiny amounts of vaccine get past the fine mesh of the blood-brain barrier, which protects the narrow blood vessels in the head from clogging. Early results claimed a 50 percent plaque clearance rate in some brain areas in transgenic mice. Unfortunately, when it was trialed on humans, the immune reaction was so pronounced that brains swelled dangerously. The latest research in Tokyo, going on as I write this, is focusing on injecting DNA that “codes for” beta-amyloid, provoking a gentler immune response. There are also trials going on for a pill that binds the amyloid and stops it from accumulating.
If Alzheimer’s proves to be a genetic condition, then genetic work is the way forward, and in terms of gene therapy we live in an age of wonders, with new diseases being identified and marked with a highlighter pen in the DNA all the time. There’s a rare inheritable form of Alzheimer’s, familial Alzheimer’s disease, that strikes people young—perhaps even in their thirties—and will go on to affect 50 percent of their children on average. It’s one very small subset of early-onset Alzheimer’s, which is classified as beginning at under the age of sixty-five. Familial Alzheimer’s has been found lurking at chromosomes 14 and 21 (and also at chromosome 1 in the American population). Regular Alzheimer’s—for want of a better description—the noninheritable kind, is thought to be indicated genetically by the gene Apolipoprotein E (APOE). APOE4, one of its four variants, is associated with high risk. If both parents carry APOE4, their children will have ten times the average risk of developing Alzheimer’s. It’s not all bad news. APOE2 appears to indicate a much lower risk than is average of developing the disease.
Genetic diagnosis and manipulation is at a stage roughly similar to that of the New World three hundred years ago. It’s still in the maps, marvels, and flag-planting era, but once domination of the genome begins in earnest, and the railroad is built to traverse it, capitulation will surely follow in a rush. For now, it’s at an early, exploratory stage, a Wild West full of frontier towns and gunslingers. The encouraging thing is that it’s begun.