Dennis Selkoe on the Amyloid Hypothesis of Alzheimer's Disease

Special Topic of Alzheimer's Disease Interview, MARCH 2011

Dennis Selkoe


According to our Special Topics analysis on Alzheimer's Disease, the work of Dr. Dennis Selkoe ranks at #1 by total cites and #5 by cites/paper, based on 136 papers cited 19,587 times over the analysis period. In our 2003 Special Topic on Alzheimer's, Dr. Selkoe ranked at #5 by total cites.

His record in Essential Science IndicatorsSM from Thomson Reuters includes 136 papers cited 19,806 times between January 1, 2000 and October 31, 2010. These papers can be found in the fields of Neuroscience & Behavior, Biology & Biochemistry, and Clinical Medicine.

Selkoe is the Vincent and Stella Coates Professor of Neurologic Diseases at Harvard Medical School and the Co-Director of the Center for Neurologic Diseases in the Department of Neurology at Brigham and Women's Hospital in Boston, MA.

Below, correspondent Gary Taubes talks with Selkoe about his career in Alzheimer's research.

SW: You've been studying Alzheimer's for over 30 years, so let's start with the big question. What's your working hypothesis of disease causation circa 2011?

My opinion is that there is an imbalance between the production and the removal of a small hydrophobic protein called amyloid beta that triggers the process we call Alzheimer's. I believe that imbalance arises from a lot of different, more fundamental causes. What I'm saying is that amyloid beta is both necessary and, at least in some cases, sufficient to cause Alzheimer's disease, but there are many other factors.

If we had to choose one, and I think the clearest, path to treatment, it would be targeting amyloid beta rather than any of these other factors, including tau, which looks like it comes downstream in the Alzheimer's cascade. So to summarize, my opinion is that it's an imbalance of amyloid beta protein in the brain that triggers or precipitates Alzheimer's.

SW: So what causes the imbalance in amyloid beta?

When you use the word "cause," it gets difficult. We have lots of genetic evidence that this amyloid beta protein imbalance triggers Alzheimer's—that's one reason that my work and others is cited a lot—but if you then ask what imbalances the amyloid beta, well, that's more complicated. Certain gene mutations imbalance its brain levels dramatically, and they cause very aggressive familial forms of the disease. Those are rare, though, and people have often criticized the amyloid hypothesis, saying that those are really rare forms, and we don't have compelling evidence that conventional Alzheimer's follows along the track of familial Alzheimer's.

"I'd like to focus on exactly how the amyloid beta protein first binds to cells and injures them. We don't know how that happens."

I don't agree with that. When I see patients in the clinic, and I still do, those with familial Alzheimer's look the same as typical Alzheimer's patients who don't have a clear family history of the disease and for whom there is no known genetic cause. When you look at the brain of a familial Alzheimer's patient and a so-called "sporadic" patient, they look indistinguishable. No expert can tell them apart. That's good evidence that the common form copies the rare familial form. But there's a lot more evidence than that.

SW: Can you give us a brief tour of the other evidence arguing for amyloid beta protein as the fundamental trigger of the disease?

One of the most striking pieces of evidence is that in the spinal fluid of essentially all people who develop Alzheimer's, amyloid beta levels go down even before they develop symptoms. This has been tested and observed around the world—in the US, Europe, Japan, China.

You see this decline in the soluble form of Abeta42 (the more self-aggregating 42-amino acid form of amyloid beta) long before the patients have symptoms. It could be three, four, even five or more years before symptoms become apparent. This lowering is due to Abeta42 protein becoming tied up on brain membranes. It sticks to the membranes of nerve and glial cells in the brain. It doesn't float in the interstitial fluid of the brain, and consequently the spinal fluid level reflects that sequestration. We have recent preclinical (mouse model) evidence for such a mechanism explains the tell-tale drop in Abeta42 in the cerebrospinal fluid (CSF).

If you ask, "Can we see the buildup of amyloid in a patient's brain?", well, the breakthrough work from Bill Klunk and Chet Mathis at the University of Pittsburgh in 2002 showed that you could put a radiolabeled dye into the body that will cross the blood-brain barrier and bind to amyloid plaques, emitting a small radioactive signal seen on a PET scan of the head. So we can now see that as CSF Abeta42 falls, it does so while less soluble amyloid (as seen by PET scanning) is beginning to build up in the brain. If you then ask, "Which of these two markers is even more sensitive to the preclinical stage of Alzheimer's disease than the other, before symptoms begin," it would be the spinal fluid level.

Another example of the apparent primacy of amyloid beta, one of the most powerful examples, is Down syndrome. That is caused unequivocally by an extra copy of chromosome number 21, and essentially 100% of people with three copies instead of two go on to get Alzheimer's disease. They get the neuropathology of Alzheimer's, and they actually get confusion, forgetfulness, and disorientation during young to middle adulthood, beyond whatever cognitive dysfunction was already there during their childhood and teenage years.

"We have lots of genetic evidence that this amyloid beta protein amyloid beta imbalance triggers Alzheimer's—that's one reason that my work and others is cited a lot—but if you then ask what imbalances the amyloid beta, well, that's more complicated."

You can say, well, there's a lot going on in chromosome 21. A whole extra chromosome, some 2,000 genes or so. But sure enough, some astute clinical researchers followed a woman who had a translocation form of Down syndrome, in which chromosome 21 is broken and a piece is translocated onto another chromosome, and that led to her having Down syndrome. She had the extra genetic material from that broken piece of chromosome 21, but the doctors noticed that when they mapped that chromosome, the breakpoint in her chromosome 21 was "south" of (telomeric to) the amyloid precursor protein (APP) gene. The extra piece of chromosome she had in all of her cells did not include the APP gene.

That's very unusual, and they followed that woman for 20 years or more, and she never seemed to be much different cognitively in her old age than she was when she was younger. Eventually she died in her mid-seventies, I believe, and she had nary a plaque of amyloid in her brain, which is in striking contrast to almost every other patient with Down syndrome. I thought that was a beautiful piece of clinical research that pinned down the notion that if you don't have an extra copy of the APP gene when you have Down syndrome, then you won't get the classic neuropathology of Alzheimer's in the brain. That was very instructive.

I could go on and on, but I feel very comfortable with the notion that we should try to treat Alzheimer's by targeting and safely lowering the amyloid beta protein. And if you ask the question why our research is so highly cited, it's because we've been doing a lot of work over a long period of time, since the late 1970s, showing how amyloid beta is made and how "it does its dirty work," in a simplistic expression.

SW: In a 2003 Q&A for Special Topics, you said that the presenilins are absolutely central to the pathology of Alzheimer's. Is that still considered to be the case or has the science changed significantly in the intervening years?

It's very much the same or even amplified. Presenilins are absolutely essential in this disease. This is the enzyme that actually makes the amyloid beta protein. Everybody has that enzyme normally. Everybody is making a little amyloid beta throughout their lives, as my lab discovered in 1992. Seven years later, with my colleague Michael Wolfe, we discovered that presenilin was the enzyme that made amyloid beta. It was just referred to as gamma secretase heretofore.

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