THINKING ABOUT ALZHEIMER'S DISEASE AS HISTORIANS

Head slumped forward, eyes closed, she could be dozing — or knocked out by the pharmacological cocktails that dull her physical and psychic pains.

I approach, singing “Let Me Call You Sweetheart,” off key. Not a move or a flutter. Up close, I caress one freckled cheek, plant a kiss on the other. Still flutterless.

More kisses. I press my forehead to hers. “Pretty nice, huh?” Eyelids do not flicker, no soft smile, nothing.

She inhales. Her lips part. Then one word: “Beautiful.”

My skin prickles, my breath catches.

It is a clear, finely formed “beautiful,” the “t” a taut “tuh,” the first multisyllable word in months, a word that falls perfectly on the moment.

Then it is gone. The flash of synaptic lightning passes. That night, awake, I wonder, Did Pat choose “beautiful?” Or did “beautiful” choose Pat? Does she know?

This heartbreaking and sad account by a husband of his wife's early slide into Alzheimer's Disease (AD) reminds us of how much we need to do to fight this. I personally think that of the myriad diseases afflicting humankind, AD is probably the cruelest of all. Pancreatic cancer might kill you in three months and cause a lot of pain but at least you are in touch with your loved ones till the end. But this is human suffering on a totally different level.

The search for the causes of Alzheimer's disease continues, and I have recently been thinking in a wild and woolly way about it from an evolutionary standpoint. While my thoughts have not been well-formed, I want to present a cursory outline here.

The thinking was inspired by two books- one book which has been discounted by many, and another which has been praised by many. The lauded book is Paul Ewald's "Plague Time" which puts forth the revolutionary hypothesis that the cause of most chronic diseases is ultimately pathogenic. The other book "Survival of the Sickest" by Sharon Moalem puts forth the potentially equally revolutionary hypothesis that most diseases arose as favourable adaptations to pathogenic onslaughts. Unfortunately the author goes off on a tangent making too many speculative and unfounded suggestions, leading some to consider his writings rather unscientific. As far as I am concerned, the one thing that the book does offer is provocative questions.

On the face of it both these hypotheses make sense. The really interesting question about any chronic disease is; why have the genes responsible for that disease endured even after so many millennia if the disease kills you? Why hasn't evolution weeded out such a harmful genotype? There are two potential answers. One is that evolution simply has not had the time to do this. The other hypothesis, more provocative, is that these diseases have actually been beneficial adaptations against something in our history. That adaptation was so beneficial that its benefits outweighed the obvious harm that it caused. While that something probably does not presently prevail, it was significant in the past. What factor could possibly have existed that needed such a radical adaptation to fight it?

Well, if we think about what it has been that we humans have been fighting the most desperately and constantly ever since we first stepped foot on the planet, it's got to be a foe that was much older than us and more exquisitely adapted than we ever were- bacteria. The history of disease is largely a history of a fierce competition that humans and bacteria have engaged in. This competition plays by the rules of natural selection, and is relentless and ruthless. For most of our history we have been fighting all kinds of astonishingly adaptable bacteria and there have been millions of martyrs in this fight, both bacterial and human. Only recently have we somewhat eroded their malign influence with antibiotics, but hardly so. They still keep evolving and developing resistance (MRSA killed 18,000 in the US in 2005), and some think that it's only a matter of time before we enter a new and terrifying age of infectious diseases.

So from an evolutionary standpoint, it's not unreasonable to assume that at least a few genetic adaptations would have developed in us to fight bacteria, since that fight more than anything else has been keeping our immune system busy and our mortality high since the very beginning. But instead of thinking about genes, why don't we think about phenotypes, about the actual effects manifested? Hence arose the hypotheses that many of the age-old chronic diseases that are currently the scourge of humanity may sometime have been genetic adaptations against bacterial infection. While the harm that is done by these diseases is obvious, maybe their benefits outweighed that harm sometime in the past.

When we think of chronic diseases, a few immediately come to mind, most notably heart disease, diabetes, Alzheimer's and cancer. But one of the best cases in point that illustrates this adaptive tendency is hemochromatosis which is an excess of iron absorption and storage, and it was this disease that made me think about AD. A rather fascinating evolutionary explanation has been provided for hemochromatosis. Apparently when certain types of bacteria attack our system, one of the first nutrients they need for survival is iron. By locking down stores of iron the body can protect itself from these bacteria. It turns out that one of the species of bacteria that especially needs iron is Yersinia pestis, the causative agent of the black plague. Now when Yersinia attacks the human body, macrophages rally to the body's defense to swallow it. Yersinia exploits iron resources in macrophages. If the body keeps iron stores from macrophages, it will keep iron from Yersinia, which however will lead to a buildup of iron in the body; hence hemochromatosis. The evidence for this hypothesis is supposed to come from the Black Plague which swept Europe in the Middle Ages and killed almost half the population. Support for the idea comes from the fact that the gene for hemochromatosis has a surprisingly higher frequency among Europeans compared to others. Could it have been passed on because it protected the citizens of that continent from the plague epidemic? It's a tantalizing hypothesis and there is some good correlation. Whether it's true or not in this case, I believe the general hypothesis about looking for past pathogenic causes that may have triggered chronic disease symptoms as adaptations is basically a sound one, and in theory testable. Such hypothesis have been formed for other diseases and are documented in the books.

But I want to hazard such a guess for the causes of AD. I started thinking along the same lines as for hemochromatosis. Apart from the two books, my thinking was also inspired by recent research that suggests that amyloid Aß peptide- a nasty aggregated protein that is a ubiquitous signature in AD brains- binds to copper, zinc, and possibly iron to generate free radicals that cause damage to neurons. Damage they may cause, but we have to note that such damage is also extremely harmful to bacteria. Could amyloid have evolved to generate free radicals that would kill pathogens? Consider that in this case it's also serving a further valuable function akin to that in hemochromatosis- keeping essential metals from the bacteria by binding to them. This would serve a 'double whammy'; denying bacteria their essential nutrients, and bombarding them with deadly free radicals. The damage that neurons suffer would possibly be a small price to pay if the benefit was the death of lethal microorganisms.

For testing this hypothesis, I need to know a couple of things:

1. Are there in fact bacteria which are extremely sensitive to copper or iron deficiency? Well, Yersinia is certainly one and in fact most bacteria are to varying extents. But since AD affects the brain, I am thinking about bacterial infections that affect the brain. How about meningitis caused by Neisseria, one of the deadliest bacterial diseases even now which is almost certainly a death sentence if not treated? Apart from this, many other diseases affect the brain if left untreated; the horrible dementia seen in the last stages of syphilis comes to mind. Potentially the brain would benefit against any of these deadly species by locking its stores of metal nutrients and generating free radicals to kill them, a dual function that amyloid could serve. I have not been able to say which one of these bacteria amyloid and AD might have evolved against. Maybe it could have been against a single species, maybe it could have been a general response to many. I am still exploring this aspect of the idea.

2. More importantly, I need epidemiology information about various epidemics that swept the world in the last thousand years or so. In the case of hemochromatosis, the causative stimulus was pinned down to Yersinia because both the disease mechanism and the pandemic are documented in detail. I cannot easily find such detailed information about meningitis or syphilis or other outbreaks.

3. In addition, while risk factors have been suggested for AD (for instance the ApoE epsilon4 gene variant), no specific genes have been suggested as causal factors for the disease. There is a clear problem with correlation and causation in this case. Also, the important role played by environmental factors such as stress and diet is becoming clear now; it's certainly not an exclusively hereditary disease, and probably not even predominantly so.

4. Most importantly, I think it is impossible to find instances of AD occurences in history for a simple reason-the disease was simply unknown before 1906 when Alöis Alzheimer first described it. Even today it is not easy to make an assessment of it. All cases of Alzheimer's before a hundred years back would have been dismissed as cases of dementia causes by old age and senility. Thus, while the causative hypothesis is testable, the effects are hard to historically investigate.

The fact that AD is a disease of age might provide some credence to this hypothesis. Two things happen in old age. Firstly, the body's immune defenses start faltering, and this might need the body to marshall extra help to fight pathogens. Amyloid might do this. Secondly, as age progresses evolution is less worried about the tradeoff between beneficial and harmful effects because the reproductive age has already passed. So the devastating effect of AD would be less worrisome for evolution. Thus, the same AD that today is thought to reduce longevity would have ironically increased it in an age where infection would have reduced it even further.

However, if AD is an adaptation especially for old age, then it begs a crucial question; why would it exist in the first place? Evolution is geared toward increasing reproductive success, not toward increasing longevity. There is no use as such for a rather meticulously developed evolutionary adaptation that kicks in after reproductive age has passed. I think the answer may lie in the fact that while AD and amyloid do affect old people, they don't suddenly materialize in old age. What we do know now is that amyloid Aß is a natural component of our body's biochemistry and is regularly synthesized and cleared from the brain. Apparently in AD something goes wrong and it starts to suddenly agglomerate and cause harm. But if AD was truly an adaptation in the past, then it should have possibly manifested itself in younger age, perhaps not a much younger age but an age where reproduction was still possible. Consider that for evolution some dementia is much preferred to not being able to bear offspring, and so AD at a younger reproductive age would make evolutionary sense even with its vile symptoms. If this were true, then it means that the average age at which AD manifests itself has simply been increasing for the past thousand years. It would mean that AD is not per se a disease of the old; it's just become a disease of the old in recent times.

So after all the convoluted rambling and long-winded thought, here's the hypothesis:
Alzheimer's disease and especially Aß amyloid is an evolutionary adaptation that has evolved to kill pathogens by binding to key metals and generating free radicals

There are several details to unravel here. The precise relationship between metals, amyloid and neuronal damage is yet to be established although support is emerging. Which of the metals really matter? What do they exactly do? The exact role that amyloid plays in AD is of course under much scrutiny these days. And what, if anything, is the relationship between bacterial infection and amyloid Aß protein 'load' and function in the body? Which bacteria really matter?

In the end, I suggest a simple test that could validate at least part of the hypothesis; take a test-tube filled with fresh amyloid Aß protein, throw in metal ions (copper, iron, zinc, etc.), and then throw in bacteria that were thought to be responsible for major epidemics throughout history. What do you see? It may not even work in vitro- I wonder if it could be tried in vivo- but it would be worth a shot.

Now I will wait for people to shoot this idea down because we all know that science progresses through mistakes. At least I do.