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Alzheimer's

By cortex on December 27, 2007.

Terry McDermott, who penned that great series on neuroscientist Gary Lynch earlier this year, has written another illuminating article on Alzheimer's. The news is bleak: scientists have yet to understand the disease. In fact, we still don't even know what causes the cellular degeneration in the first place:

It's been 101 years since Alzheimer's disease was first theorized, and 30 years since the federal government began funding research on it, spending, to date, more than $8 billion. Private industry has spent billions more. What has been learned?

The answer is perplexing. There have been more than 35,000 scientific papers published on Alzheimer's just in the last decade. They include hundreds of impressively detailed descriptions of purported disease mechanisms. But in all that wealth of information, there are some rather obvious gaps.

For example, the leading hypothesis of the cause of Alzheimer's, called the amyloid hypothesis, is centered on the overproduction, or inadequate clearance, in the brain of a protein called beta amyloid. Fragments of the protein aggregate into clumps called plaques. These plaques were first observed more than a century ago by the man after whom the disease is named, Alois Alzheimer.

For most of the century since, scientists have believed the plaques were associated with the disease. But to date, they don't know whether amyloid plaques are the cause of the disease or a result. They don't know whether they are vital to the progress of the disease or incidental. They don't even know whether their presence is indicative of the disease.

A rival idea, called the tau hypothesis, is no more definitive. Where beta amyloid generally aggregates outside brain cells, the protein tau aggregates into fibrous structures, called tangles, inside the cells.

The processes by which either amyloid or tau cause brain cells to malfunction, and in some cases die, are neither well understood nor completely coincident with observations of the disease itself.

It's now been almost a decade since the decade of the brain, and while we know more than ever about the three pounds of gelatinous flesh inside our head, the lack of scientific progress on major brain diseases has been humbling. Prozac, a drug invented fifty years ago by accident, remains our most effective treatment against depression. Nobody really knows what causes schizophrenia, or if schizophrenia is even a single disease. We have no idea what triggers Parkinson's. Alzheimer's remains poorly understood. Autism is a mystery. The list goes on and on. Perhaps one day we'll be able to fix the brain and prevent its breakdown. But I'm not holding my breath.

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The NY Times also ran an article on Alzheimer's yesterday, which reported that we currently spend a billion dollars on drugs to "treat" a disease that in fact we know very little about. In the same article, it was noted that if the contested amyloid hypothesis leads nowhere, we are basically back to square one.
I noticed, looking at the right side of your home page that the current "five most emailed science blog posts" include two which allude to Alzheimer's (specifically, the claim that fish oil reduces the risk).

The statement about Prozac makes me sigh. We know more about how disease progresses, but we've learned very little about how to fix things. Human machinery is so complex, especially when one considers how adept the body is at maintaining homeostasis (think of all of the compensatory changes the brain makes when we try to fiddle with its biochemistry). How often do we actually discover drugs, versus stumbling onto them?

It makes me think of Stephen Wolfram - who'd probably catalog Alzheimer's research as another piece of evidence to show that reductionism isn't working.

I think the original post and the first two comments are confounding, not curing diseases and not understanding them. We know a lot more about Alzheimers than we did even 10 years ago. All research does not focus on plaques and tangles. Drugs like Aricept are cholinesterase inhibitors and have been shown to delay the decline. We are getting better at early detection, which is key to treatment. One key to the "cure" for Alzheimers is that we don't need to cure it to make a huge difference. Through early detection and peripheral treatments, if you can delay the worst aspects of the disease 10 or 20 years many will die before the symptoms significantly effect their lives. This is essentially a cure.

There is nothing wrong spending billions of dollars to treat an uncurable disease. Most of that money is going to things like 24-hour care and not pills. Until we have a cure, should we just not spend the money to care for AD patients?

To say treatments and understanding of things like Autism haven't advanced is ridiculous. In 1980, there was barely an organized way to diagnose the disease. Now we have much cleaner diagnostic tools that help categorize and direct treatments. Agressive and personalized behavior based treatments have been shown without a doubt to benefit children (not cure). If you ignore the anti-vaccination fundamentalists, we know autism has a clear genetic component and symptoms clearly appear between 18-30 months (with some studies showing symptoms in a subset of children at 5 months).

Just because advances are slow, doesn't mean they aren't happening. The world is a better place for someone with a brain disease now than it was 15 years ago.

Thanks for your comments. As I note in the post, we've learned a lot about these various brain diseases. And yet, I think it's important to note that our new knowledge has, in many cases, made us even more aware of just how difficult these diseases will be to cure. Ten years ago, the beta amyloid hypothesis was much less controversial than it is today. We had a clear plan for curing Alzheimer's: prevent plaque accumulation. Today, no such consensus or plan exists. A similar pattern is at work with syndromes like autism and schizophrenia. Our new knowledge has revealed the sheer complexity of these disorders, and shown us how these syndromes (which are probably a collection of different syndromes with similar symptoms) are caused by a vast number of interrelated genes, environmental factors, etc. In other words, there is no smoking gun. Obviously, over the long term such confusion is a necessary stage of progress. But it's still worth reminding ourselves just how much remains unknown. And what we do know we don't always understand.

Hi Jonah, I appreciate the candor in your statement--indeed, the Alzheimer's field is replete with hype and exaggerations and short on measured, realistic expectations. I wanted to give you a head's up on a book that I've co-authored, which is coming out on January 8th, 2008, called "The Myth of Alzheimer's: What You Aren't Being Told About Today's Most Dreaded Diagnosis." My co-author is Dr. Peter Whitehouse, a neurologist at Case Western Reserve University, whose discoveries in the '80s led to the development of the first drugs for AD (cholinesterase inhibitors). In our book we challenge the medical-industrial complex that has powered the Alzheimer's movement, and strive to convey a more sober, realistic, and yet hopeful message about brain aging, the tone of which seems quite consonant with your post. Don't want to self-promote, but I do feel that you would be sympathetic to what we're trying to do. Please visit our website, which is still a work in progress (www.themythofalzheimers.com), and visit the amazon posting, which gives a brief overview of the book (http://www.amazon.com/Myth-Alzheimers-Todays-Dreaded-Diagnosis/dp/03123…)
Would greatly appreciate your opinion on the book if you get a chance to read it. Also, I'm developing a blog and learning the ropes, and would eventually like to "cross-link" (if I have the jargon right) with your blog. Anyhow, all the best in the new year,
take care,
Danny George

Jonah,
I think you overstate the past Alzheimer's theories and understate our current understanding. The field was never 100% behind plaque removal and even when that was where the main drive of research was going, there was healthy skepticism. Perhaps lay press was a bit more optimistic and focused 10+ year ago, but that's not where you go to get a true understanding of a field.

Medical research is never fast. The "war on cancer" was declared over 40 years ago. While we've virtually given up on the idea of "curing" cancer we've realized it's a much more complex and diverse grouping of problems - some of which we have essentially cured when they are caught early enough. Compared to the brain, heart disease should be really simple to solve, but even for the simple question of prediction, we keep changing the optimal metrics every 5 years. Few medical problems have simple solutions and classifying complexity IS advancement.

Danny,
the general benefit of cholinesterase-inhibitors for memory (or attentional allocation) improvement is clear, but from the scientists' perspective, anyone that tries to claim that research in a certain direction is all a myth from the " medical-industrial complex" really does not make me want to read it. If your book claims that research of AD is going in the wrong direction, then "myth" is inappropriate and if you claim that AD doesn't exist and it's just normal aging, there are way too many quality studies proving that wrong.

It's now been almost a decade since the decade of the brain, and while we know more than ever about the three pounds of gelatinous flesh inside our head, the lack of scientific progress on major brain diseases has been humbling. Prozac, a drug invented fifty years ago by accident, remains our most effective treatment against depression. Nobody really knows what causes schizophrenia, or if schizophrenia is even a single disease. We have no idea what triggers Parkinson's. Alzheimer's remains poorly understood. Autism is a mystery. The list goes on and on. Perhaps one day we'll be able to fix the brain and prevent its breakdown. But I'm not holding my breath.

Glad you are not going to hold your breath! LOL! Even though it might sound trite. I have a computer background and have a great deal of faith in the idea that as the machines move up hundreds of times faster we are going to be able see correlations in data that were imperceptible before. Many fields have been at the point where they weren't even sure if they got the questions right, let alone knowing the answer before.
It took persistence, dedication and time! But those 3 together can form an awesome triangle! Look at the thousands of times Edison tried to find a filament for the lightbulb.
Everyone who said to him it could never be done because it never had been done have passed on, and we sit in the light, enjoying the determination.
Dave Briggs :~)