Of course, there is always the possibility that researchers at Penn or elsewhere will discover a new dimension to the problem. Steve Arnold, for one, wonders whether both amyloid and tau are “secondary to something else” in the more common, late-onset forms of Alzheimer’s.

“That worries me, that there’s some kind of change in the way older cells handle misfolded proteins,” he says. “I think that proteins misfold all the time, and we have a whole waste-clearance system for getting rid of them. And that changes with time. And I wonder whether the common forms of Alzheimer’s disease are essentially a waste-management problem, that the cell can’t clear the misfolded proteins, and it starts to choke on itself.”

Some epidemiologic studies show that “about 10 percent of people have a head full of plaques and tangles, severe pathology in the brain, and yet they’re not demented,” Arnold points out. “And on the other hand, you have maybe 10 percent or 12 percent of people whose brains are clean of pathology, and yet they’re very demented. So there are other biological factors going on that seem to determine this.”

One possibility is that some people are simply “more resistant to the toxic effects of plaques and tangles,” he adds. But there could be other explanations. One, believe it or not, involves insulin.

“It looks as though there are major abnormalities in insulin-signaling in brain cells,” says Arnold. “One hypothesis that we’re following up is that amyloid-beta oligomers [two or more conjoined molecules] actually damage the ability of insulin to signal. Some people have referred to Alzheimer’s disease as Type III diabetes. We have to flesh this out, but given how much we know about diabetes—and much of the knowledge coming from the diabetes and metabolism people here at Penn—it opens up new therapeutic avenues to think about. In Alzheimer’s we’re talking about insulin resistance in the brain. Can we use some of the same medicines that are being developed to sensitize insulin receptors to perhaps prevent or slow down Alzheimer’s disease?”

In the meantime, assuming that tau and beta amyloid are still among the usual suspects, the key is to discover their presence in the brain as early as possible. Hence the importance of biomarkers.

This past October, the NIH announced it was expanding the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a public-private partnership, to find biomarkers for Alzheimer’s. This phase of the study will involve 550 volunteers “in the earliest stages of cognitive impairment,” said National Institute on Aging Director Richard Hodes, and “should give us new insights into the onset and progression of Alzheimer’s disease.”

“If you’re trying to come up with a molecule or drug that diminishes the formation of senile plaques, ideally you want to get into the patients a decade before they show dementia, because that’s when senile plaques are formed,” says Kurt Brunden. “One of the clear potential advantages of tau-based therapy is that it appears that the tau tangles form later in the disease, more in concert with the onset of dementia. Unlike the plaque-based therapies, you can probably treat with a tau-based agent at an early stage of the disease—but one that at least is diagnosable at this point—and still have an impact. That’s our hope.”

 

Oddly enough, tau was the first component of Alzheimer’s that could be identified as a potential biomarker, says Lee. That was back in 1995.

“We and others have shown that you can look at the level of tau in the spinal fluid and be able to distinguish between patients that have Alzheimer’s disease and the control group,” she says. “Then, later on, in the late ’90s, it was shown that the beta amyloid, too, could be a biomarker for Alzheimer’s disease.” But it wasn’t until two years ago—thanks to a great deal of work by Les Shaw, professor of pathology and laboratory medicine and co-director of the Penn ADNI Biomarker Core—that an effective, accurate test measuring tau and beta amyloid in cerebrospinal fluid was standardized and validated, and the results published in Annals of Neurology. The test proved to be 87 percent accurate overall, and 96.4 percent accurate among those with autopsy-confirmed Alzheimer’s.

“You have to have the right samples, with very careful longitudinal follow-up, to be able to compare the tau and a-beta in the spinal-fluid at baseline—when you actually complain of a memory impairment—to a year later, and determine the changes in your spinal fluid,” explains Lee. All that standardization led to a test that can, by “looking at changes in the spinal fluid tau and a-beta level, predict whether or not you have converted, or you will convert, to Alzheimer’s disease.”

On January 20, the FDA conditionally approved a new PET-scan technique for detecting amyloid plaques in the brain. (Final approval is conditioned on the development of an effective training program for reading the scans.) The scan uses Amyvid (florbetapir), a radioactive tracer that was developed and patented by Penn and licensed by Avid Radiopharmaceuticals, a small biotech company based in the University City Science Center.

Avid, which was purchased this past December for $800 million by Eli Lilly, was founded six years ago by Dan Skovronsky Gr’00 M’01, and its chief scientific advisor is Hank Kung, a former Penn professor of radiology and pharmacology.

“Dan Skovronsky’s original experiments were done in our laboratory, on this floor, and discussed in our conference room back in ’98, ’99,” says Trojanowski. “Dan was a graduate student of Virginia’s when he was doing this work. Then, while training with me in neuropathology, he went on to start Avid, which raised $70 million, which enabled him to hire 60 people over on Market Street. So when people in Congress discuss budgets, they should be mindful that some of the things we do not only have an impact on health and lowering the cost of healthcare, but also generating new industries such as Avid Radiopharmaceuticals, which has been a blockbuster success.

“In other words,” he adds pointedly, “creating jobs.”



Two months ago, President Obama signed the National Alzheimer’s Project Act (NAPA) into law. It creates, in the words of a statement by the Alzheimer’s Association, a “coordinated national strategy to confront one of America’s most feared and costly diseases,” one that “will only plague more baby boomers as they age.”

Using the recommendations of the Alzheimer’s Study Group—an independent, bipartisan panel that will evaluate the government’s current efforts to combat the disease—NAPA will produce a national strategic plan to confront the epidemic and establish an inter-agency council to work with the Department of Health and Human Services to give a full assessment of what needs to be done to cope with the disease on multiple fronts, including care, research, and support.

“I think it’s good news, in terms of expecting or hoping that there may be an increase in funding,” says Lee. “But at the same time, our economy is not good, and it’s unclear whether there would be an appropriation of funds for this effort. So it’s all very well that Obama signs this bill. But without funds or ways in which we can implement what is in the bill, it’s really purely symbolic.”

“You could be cynical, or maybe realistic, and say it’s not going to have much of an impact, but I think it’s a big step forward,” says Trojanowski. “It’s symbolic right now, but I’m hoping that someone who occupies the office of the Alzheimer’s czar would know a lot about Alzheimer’s, wouldn’t just be a political hack and keep the seat warm, and would be an eloquent bully, a fear monger, seductive, cajoling, to do what I think this country absolutely has to do to see Alzheimer’s disease for the epidemic that it is, to save our country from financial disaster.”

 


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COVER STORY: Untangling Alzheimer's By Samuel Hughes
©2011 The Pennsylvania Gazette

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