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 By studying the role of oxidative stress in Alzheimer's disease, you are one of the few highly cited researchers not focusing on amyloid or tau. What is it about your approach that has led you off the beaten track in this field?

I have a pretty diverse background, and it plays a major role in the way I approach problems. I was trained initially as a classical biologist with a strong emphasis in chemistry. I was very interested in understanding environmental biochemistry, and I ended up working with sea urchins as a model system. I did a post-doctoral fellowship in cell biology and there I learned more about applied research. I was studying cytoskeletal abnormalities in disease processes.

 Why cytoskeletal abnormalities?

From the late 1970s to the early 1990s, there was a lot of interest in calcium regulating oxidative stress and cytoskeletal interactions. So I moved from oxidative stress to the cytoskeleton because of this calcium link. When I was looking for a faculty position, I got employed because of my understanding of the cytoskeleton. And that is how I got into Alzheimer's disease.

The actual work I do isn't that different from what I used to do in marine biology. It's just that I don't do work in marine organisms anymore; I work in the human brain. But because I was trained as a marine biologist and not a biologist studying marine organisms, this made a difference in how I approach problems.

 How would you define that difference?

Annual reception honoring recipients of scholarships in the College of Sciences. View additional images of this event.

It has to do with whether you understand organisms in the context of their environment. If you go to a zoo and see a tiger and you go to India and see a tiger, you're seeing a tiger in both cases. But the only time you really appreciate a tiger as an organism is when you go to India. Organisms respond to the context they're in. It's true for people, too. And that's relevant to how one thinks about Alzheimer's. People develop these changes in their brains as they get older. They're not just imposed by genes.

 Are you implying that the environment plays a major factor in influencing the disease process?

There are environmental influences, but the important point is that people's brains change as they get older all the time. As you get older in life, you realize you're not the same person you were when you were young. I don't mean you're the same but diminished. You're different. Everything is changed.

A lot of my work relates to the biology of Alzheimer's disease. That's been the central focus. Even though the publications are about oxidative stress, they're related to what type of changes people undergo as they get older and how they adjust during Alzheimer's disease.

 Is oxidative stress a by-product of the disease process?

Some of it is, but not all of it, because we see it in everybody after the age of 35.

 Is oxidative stress the earliest event you see in Alzheimer's disease?

It's one of the earliest events. It occurs prior to disease initiation, prior to the onset of symptoms. And during mild cognitive impairment, oxidative damage is actually higher than later in Alzheimer's disease. Although we haven't published that observation yet.

 So you don't think amyloid accumulation triggers the disease process as Dennis Selkoe suggests?

His view and ours are diametrically opposite.

 OK, tell us yours.

Ours is that amyloid is a response to the disease, not the cause of the disease. Amyloid is not irrelevant. It's very, very important. So I don't differ from Dennis in that sense, because we both believe amyloid is important.

Why? There are several reasons. One is vaccines. When amyloid is removed from brains using vaccines, it doesn't help patients. In fact, patients got slightly worse. This is true in all the studies. Further, when one sees amyloid deposition in the brain, oxidative damage decreases. So there's an inverse correlation. Whether oligomers or fibers, when we see amyloid increased, we see a decrease in the levels of oxidative damage. One important mechanism for amyloid's apparent antioxidant activity is that it binds copper and redox silences it.

With my colleague Mark A. Smith, also a highly cited person who unfortunately died in December, we've written probably about 100 publications questioning the amyloid-cascade hypothesis.

"If I had to make one guess at this point, I'd say Alzheimer's disease is a metabolic disease."

The amyloid cascade hypothesis is a very simplistic view that was useful to consolidate many observations under testable hypotheses. Failure of those tests has now put the hypothesis in question. Unfortunately the cascade hypothesis is fundamentally an abiological concept. It goes against evolutionary selection; it does so by proposing a well-adjusted organism would produce a response that has but a detrimental effect. For a response to develop in the body it must have some adaptive value.

 So you're presuming it's a response to oxidative stress?

Exactly. I'm proposing amyloid is an adaptive response, based on some of what we already discussed.

 That oxidative stress goes down when amyloid accumulation goes up?

That's one—oxidative stress goes down when amyloid goes up, and when we remove amyloid people actually get worse. Again, I'm not proposing the amyloid is irrelevant. And we're not the only ones who question the amyloid cascade hypothesis. Many people do. Most say it's secondary. Some say it's irrelevant. I think it's a critical part of the disease process, but not the trigger.

 So your hypothesis would be that oxidative stress triggers the disease process?

Not exactly. Our hypothesis is that oxidative stress is a window for looking at the disease, just as amyloid is also a window. People elicit a number of responses as Alzheimer's develops. The key thing to determine is where the oxidative stress originates. There has to be an abnormality that predates oxidative damage. Amyloid is not the primary abnormality because amyloid, if anything, reduces oxidative stress.

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