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Understanding Alzheimer's Disease

An Interview with Dr. William L. Klein

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The Klein lab group at Northwestern’s Center for Advanced Molecular Imaging, courtesy of Dr. William L. Klein (pictured top row, far left)

Dr. William L. Klein is a professor of neurobiology and neurology at Northwestern UniversityAfter graduating from MIT in biology, Dr. Klein carried out pre-doctoral studies in protein biochemistry at UCLA with Paul Boyer (Nobel Prize, chemistry) and postdoctoral studies in molecular neurobiology at the National Institutes of Health with Marshall Nirenberg (Nobel Prize, physiology and medicine).

Dr. Klein and his colleagues have pioneered the concept that Alzheimer's disease is caused by amyloid beta oligomers, small neurotoxins that target particular synapses and cause their functional and structural degeneration.

Science in Society spoke with Dr. Klein to learn more about his decades of work on Alzheimer’s. In this in-depth Q&A, he discusses how this devastating disease affects the brain, as well as the advancements made toward a treatment and the need for more funding for research.

I feel like often people use the word Alzheimer’s to describe senility in general. Is Alzheimer’s disease different than other types of dementia or can all dementia be classified as Alzheimer’s?

It’s a question a lot of people are puzzled by. Dementia, what we used to call senility, is a type of abnormal behavior. Dementia is due to brain damage that can be caused by Alzheimer’s disease, and by a number of other brain diseases and conditions as well. So Alzheimer’s is a type of dementia. Different sorts of brain damage – due to Parkinson’s disease or Huntington’s disease, or even diabetes – can result in similar but not identical demented behavior. But Alzheimer’s is the major cause – it accounts for many more cases of dementia than the other diseases.

There’s an interesting historical side to your question, too. Dr. Alzheimer’s first dementia patient, documented in 1906, was in her early 50s. For decades, neurologists thought Alzheimer’s was an extremely rare disease found only in younger or middle-aged people. It was called “presenile dementia” – an unusual type of dementia that showed up before people grew old. Not until the 1990s did it become clear that Alzheimer’s disease can show up early or late in life, and that it’s basically the same disease. In fact, it’s much more common late in life.

What does Alzheimer’s disease do to the brain?

Alzheimer’s is a progressive disease. It causes brain cells first to malfunction, then to degenerate and die. At its beginning, Alzheimer’s selectively affects brain cells linked to forming new memories. Later it spreads, and the consequences grow increasingly catastrophic. At end stages of the disease, even the neural circuits underlying the simplest behaviors, such as eating and getting dressed, no longer work.

How does this terrible damage get started? It’s widely believed the cause is a neurotoxin my collaborators and I discovered at Northwestern a number of years ago. Alzheimer’s pathology is complex, but it appears the first important changes have a lot to do with these toxins, which we called “ADDLs” (pronounced addles). Chemically they’re called “amyloid beta (or Abeta) oligomers.”

Over the last decade, we’ve learned how ADDLs attack the brain. From our cell biology experiments, and our experiments with Alzheimer’s models, we found that ADDLs target the brain’s synapses. That’s where nerve cells talk with each other, and it’s where memories begin. Some of our most important experiments showed that ADDLs undermine the molecular basis for memory formation. The toxins sit on synapses and inhibit their responses to signals that carry information. The brain needs that signaling to form new memories – and it just can’t happen.

We’ve also learned the disease process begins very early and progresses over a surprisingly extended time. Brain damage begins long before memory problems and other symptoms show up. It’s a progressive disease - brain damage and behavior get worse and worse. Ultimately, it’s fatal. In fact Alzheimer’s is a leading cause of death. My colleagues and I would like to be able to detect the brain’s earliest changes – to get an early diagnosis. If you can identify problems early, you’ve got a better chance of fighting them. Just like in any disease.

Previously people thought plaques caused Alzheimer’s, and it wasn’t until you discovered this toxin that you realized that might not be the case?

That’s right. For decades, the most powerful hypothesis in the Alzheimer’s field was the “amyloid cascade.” Alzheimer’s-affected brain tissue is riddled with amyloid plaques – even Alzheimer saw these large deposits in the brain tissue of his first patient. Plaques are made of really long stringy molecules (“amyloid”) that have clumped together. For years, scientists thought plaques were responsible for causing dementia. Now we know this isn’t so. Most of us think the real culprits are ADDLs, the Abeta oligomers. Yes, plaques are abnormal, but they’re found in lots of normal people, who have no dementia. This is one reason why the plaque hypothesis was never fully accepted.

So, if you want to know if someone has Alzheimer’s, you have to look for these Abeta oligomer toxins in the brain?

Right now, there are no laboratory tests that confirm the disease. Outstanding clinics like Northwestern’s (at our Cognitive Neurology and Alzheimer’s Disease Center) have an accuracy rate of over 90 percent, but it’s impossible to know for sure if someone has Alzheimer’s disease. Difficulty in diagnosing Alzheimer’s is a serious problem.

We’re very excited about new probes we’re developing to visualize Abeta oligomers in the brain by neuroimaging. The project is being led by Kirsten Viola, a researcher who’s been with my team for more than 20 years. Being able to see Abeta oligomers in the brain would be a breakthrough. Oligomers show up early in the disease, and they instigate the brain cell damage leading to dementia.

Some of our NU colleagues who specialize in nanotechnology have been working closely with us on this project and other diagnostics research (including Vinayak Dravid, Rick Van Duyne, and Chad Mirkin). Northwestern has an amazing facility for this work – CAMI, the Center for Advanced Molecular Imaging, headed by Tom Meade. CAMI’s helping us push this work forward. Our pilot experiments show we can image oligomers by MRI in animal tests. One day we’ll be able to image them in patients. I’d bet on that.  

I read that Alzheimer’s can be inherited, and that there are genetic mutations that put you at risk, such as APOE4. Do such factors really put you at a higher risk?

There’s an inherited form of the disease, but it accounts for only a small percent of the patients. These people have specific mutations. If you have just one of these mutations, you will get Alzheimer’s disease. But inherited Alzheimer’s is rare.

On the other hand, there are risk factors like APOE4. If you have two alleles that code for APOE4 you’re a lot more likely to get Alzheimer’s disease. But it still doesn’t mean for sure that you will get Alzheimer’s, you’re just at higher risk.

So, if your grandmother had it and your mother had it, is it fair to say then that you’ll probably get it? Or, could you possibly be absolutely fine?

It could completely pass you by – you could be absolutely fine. But, it’s evidence of increased risk. Older reports indicated that wasn’t the case, but now it seems if you’ve got a lot of Alzheimer’s disease in your family, you’ve got a bigger risk. But it doesn’t mean you will get it. There is a big difference between might and will.

How early can somebody come down with the symptoms?

I think there was a pair of brothers who came down with the disease in their 20’s. People who have inherited mutations are most vulnerable to early onset Alzheimer’s disease – and it’s pretty rare. Overall, we tend to think of Alzheimer’s as a disease whose symptoms start to accelerate after age 65. For people over 85, the incidence is about 1 in 2. That’s pretty scary.

What methods might be used to treat, and potentially remove, these toxins?

I’m excited about a potential treatment that’s coming out of our earlier work at Northwestern. Around ten years ago, our team began developing antibodies that neutralize ADDLs – that could render them harmless. Our findings led to a large-scale partnership with Merck. Merck took our antibody program, invested about $50 million in research, and produced a highly effective antibody that can be used in humans. It works beautifully in all the preclinical tests - the antibody gets into the brain, targets oligomers and neutralizes them. The FDA has cleared the way for the antibody to be tried in humans, in clinical trials. But trials are expensive, and Merck had to drastically cut back their Alzheimer’s program, so we have to get the antibody to the clinic without them.

Would you need to get the antibody treatment every year, like a flu shot, or is it something you could get once?

We don’t know yet. I think you’d probably need regular treatments. But they could be really simple and non-invasive. In animal studies, the antibody is amazingly potent if delivered right into the brain. We’re trying to develop methods that will maximize brain access. One interesting method is a nasal spray. It’s possible to get our antibodies into the brain by administering them through the nose. The antibody bypasses the blood brain barrier and gets quickly to the toxins in the hippocampus, where memory is first affected. I’m optimistic this new strategy could make treatments really effective.

Would you start receiving the vaccine as soon as you show signs of Alzheimer’s or would it be something you can take before you exhibit symptoms?

This is why we need to develop an early diagnostic – you don’t want to treat someone with a healthy brain! We need a test that tells neurologists when their patients are building up toxins. We’re working to develop our nasal spray method for diagnostics, putting probes onto our antibodies so they can be used for MRI or PET imaging. As I mentioned, we’ve tested a prototype, and it can distinguish an Alzheimer’s mouse from a normal mouse!

When might this vaccine be available?

Northwestern has licensed a biotech called Acumen to develop the vaccine. Acumen, which Grant Krafft, Tuck Finch and I started in the 90s, is working with venture capitalists to raise money for the clinical trials. We’d like to start the trials as soon as possible. It would take seven or eight years to get FDA approval. I want to mention that my lab also is working on new strategies to develop different approaches to Alzheimer’s therapeutics. You never know ahead of time if your predictions (and hopes) will prove true. That’s science.

Some people believe there isn’t enough funding going into Alzheimer’s research. Do you agree?

Absolutely, and it simply makes no sense. Alzheimer’s is the third most costly disease. It removes more than 200 billion dollars from our economy every year. The research dollars that are being spent are about half a percent of that.

There’s just not enough money to do the research. I recently got back from reviewing grant applications for NIH. There were 114 proposals on how the environment might contribute to Alzheimer’s. How many will be funded? Seven! Not only does this ridiculous funding rate slow down research – it’s going to discourage people from trying to solve the problem. I spend way too much of my time writing grant proposals. If we can’t get more research dollars, and find an effective treatment, Alzheimer’s by 2050 is going to cost us a trillion dollars a year on care. To solve the problem, we’re investing a couple hundred million a year. This is really a foolish imbalance.

Do you think the disease will become more prevalent?

Yes. Our population is getting older, and late-onset Alzheimer’s is one of the fastest growing, if not the fastest growing, disease. And individuals with Alzheimer’s can linger 15 years or more with dementia. Even though they’re no longer able to take care of themselves, for many years they’re still individuals with real feelings. They’re still our parents and our grandparents, our husbands and our wives, and we have to help and care for them.

What recommendations do you have for youth who are interested in doing the kind of work that you do?

First thing is to figure out what intrigues you, to really get in touch with your interests. There’s a saying from the famous science fiction writer Isaac Asimov, who also was a biochemist. He said “Science doesn’t begin with ‘Eureka! I found it!’ but rather with ‘hmm, that’s funny.’” You have to be really intrigued by the mysteries to sense what might be happening in the unknown. You have to care enough about your mysteries to find their solutions.

Is there anything else you’d like to add?

All of us senior scientists have to remember that it’s the junior scientists, the technicians and students and postdocs in our labs, who are really making things happen. And when you’re a student in a lab, you have to remember you’re doing work that is real and important and needs to get done…and the rest of us are grateful for that.

Additional information:

The Klein Lab at Northwestern University
20th Annual Alzheimer Day
2011-2012 Alzheimer's Disease Progress Report from the NIH
Alzheimer's Association
"Why Can't We Prevent Alzheimer's?" by Jim Kozubek (The Atlantic)

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a very brief article on

<p>a very brief article on alzheimers. one should have access to such health related articles. The best point is that "Alzheimer’s can be inherited, and that there are genetic mutations that put you at risk".</p>

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