When Alois Alzheimer examined the brain of a patient known as Auguste D. in 1906, he found that brain cells had died “on an immense scale,” as Ralf Dahm, author of Alzheimer: 100 Years and Beyond, put it. “In the neurons that remained Alzheimer noticed thick, strongly staining fibrils. Moreover, the cortex was full of plaques of unknown composition.”

Those plaques and tangles are still the dominant feature of the disease that bears Alzheimer’s name. But after his seminal discoveries, not much happened on the Alzheimer’s front. The disease was first mentioned in The New York Times in the 1930s, Trojanowski notes; the second time wasn’t until the ’50s.

“For many years Alzheimer’s disease really was not on anyone’s radar screen,” says Lee. “Fifty years ago people don’t even think it’s a disease. They just think that Grandma is getting old and a little bit forgetful.”

It wasn’t until 1976, when Robert Katzman—an Alzheimer’s activist and neurologist at UC-San Diego who founded the Alzheimer’s Association and the Alzheimer’s Disease Research Center—wrote an editorial titled “The Prevalence and Malignancy of Alzheimer’s Disease” in Archives of Neurology that the medical community really woke up to the seriousness of the situation.

For Trojanowski, the “modern molecular era of Alzheimer’s disease research” began in 1984 when George Glenner and Cai’ne Wong isolated the beta-amyloid peptide from the amyloid deposits in the brains of Alzheimer patients. “It wasn’t genetics,” he says. “It wasn’t fancy-schmancy GWAS [genome-wide association study]. It wasn’t proteomics. It was old-fashioned biochemistry and neuropathology.” From that discovery, he adds, “we went to identifying the mutations in the gene that caused Alzheimer’s disease. And from there we went to animal models and on to drug discovery.”

Thirty years ago the late, great medical essayist Lewis Thomas called Alzheimer’s “the disease of the century.” While AIDS may have justifiably stolen the spotlight in the 20th century, the demographics and staggering costs associated with Alzheimer’s make it well-positioned to reclaim the title in the 21st.

“When Alzheimer described Alzheimer’s disease in 1906, life expectancy was 48, and the top 10 or 20 causes of death were infectious diseases,” points out Trojanowski. “A hundred years later, people are living to an average age of 78 in developed countries. And now Alzheimer’s, which was ignored, has become an epidemic. Alzheimer’s has replaced diabetes as the sixth leading cause of death in developed countries.

“The current [global] cost of Alzheimer’s disease is $604 billion,” he adds. “If those costs were the economic output of a country, then the cost of Alzheimer’s care would mean that Alzheimer’s is between Turkey and Indonesia as the 17th-largest economy in the world. If it were a company, it would be the largest company in the world, larger than Walmart and Exxon Mobil. It’s affecting China, Southeast Asia, Australia, Indonesia. So it is a global problem. A global epidemic—with horrendous costs.

“We really owe it to ourselves and future generations to create a world without Alzheimer’s disease,” he adds. “And I think we can. Twenty years ago I wouldn’t have said that. We didn’t know enough. When asked at support groups by families that had an Alzheimer’s patient, I would almost tearfully have to say, ‘I have no idea.’ As a physician, to admit that there was nothing that you could do—and that you had no idea when something could be done—was emotionally difficult. And now it’s changed so dramatically that I say the cure will come as quickly as the American people want it to come.”



In 1991, the same year they found conclusive proof that the tangles in Alzheimer’s were formed from tau proteins, Lee and Trojanowski founded the CNDR (www.med.upenn.edu/cndr), which has become the main nerve center of their work. It’s one of those “centers without walls,” and its 55 researchers and support staff collaborate with another 40 faculty members around the School of Medicine and across the University. (It should be noted that the School of Nursing does important work related to Alzheimer’s and other neurological diseases that doesn’t fit into the scope of this article.) They conduct clinical and basic research across a swath of disciplines, probing the causes and mechanisms of brain dysfunction and degeneration in Alzheimer’s, Parkinson’s, frontotemporal disease (FTD), amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease), and other neurodegenerative disorders.

This is not just a dumping ground for research projects that can’t find a home anywhere else, by the way. There are key pathological connections between those disorders, whose common thread is the “fatal attraction” of certain brain proteins. Five years ago, for example, Lee led an international team that identified a misfolded protein, TDP-43, that causes both ALS and FTD.

In creating the CNDR, Lee drew on organizational skills learned while earning her MBA from Wharton in her spare time. That was in the early ’80s, when she was concerned about the Reagan administration’s plans to privatize the NIH and thought she might need to hone her executive skills.

“At a subconscious level it probably helped me tremendously in terms of organizing the center,” she says. “At that time we have small labs, and John has maybe three or four people; I have maybe the same number of people working for us. Since the late ’80s he and I really put our heads together and said, ‘How can we organize an infrastructure so that we can really, truly study Alzheimer’s disease and other neurodegenerative diseases?’”

That infrastructure, she adds, “turned out to be extremely valuable.”

“I can’t really think of another university in the United States—or anywhere in the world, really—where there are centers of excellence in Alzheimer’s, Parkinson’s, frontotemporal disease, and ALS,” says Trojanowski. “And where one or two exist, they often don’t interact as seamlessly as we do. I don’t know if you want to attribute to this Benjamin Franklin, but there is a culture of collaboration at Penn, of collegiality, that makes it possible to reach across departments, disciplines, schools.”

He points to the new integrated neurodegenerative disease database (INDD) that incorporates massive amounts of information from living patients and provides a “valuable tool for generating data sets in comparative studies on several neurodegenerative diseases,” in the words of an abstract for the Alzheimer’s Association’s newsletter. This is the kind of achievement that might not make for front-page headlines, but it makes scientists very happy—and helps them be productive.

When those patients die, “we then have autopsy information on them, we have genetics,” Trojanowski explains. “And this is for each of the four disease categories. I know of no common database like this in the country where people have said, ‘We’ll all put our data into the same database archives; we’ll all have access to it; we’ll be able to work with it and publish with it and use it to do collaborative studies as well as individual studies.”

“We wanted to develop the infrastructure [of the CNDR] because we want to study the brains of patients with the disease,” says Lee. “So how do you get the brains? John is a doctor, but he’s a neuropathologist. He doesn’t see patients. So we said, ‘OK, we’ve got to collaborate with a neurologist and also other individuals like psychiatrists that see these patients.’”

Not that those colleagues are complaining. Steve Arnold, a professor of psychiatry and neurology and director of the Penn Memory Center, cites the combination of “extraordinary talent,” the “vibrant, open-source atmosphere,” and individual collegiality as a key reason behind the success of the Alzheimer’s and other neurodegenerative-disease programs at Penn.

“It’s very easy to find people who are interested in the same types of things that you’re interested in, and who are happy or eager to collaborate and work with you,” says Arnold. “The collaborative atmosphere is really great—unlike some other institutions, where people are so balkanized.”

“We’ve got a great group here that represents a lot of the areas—from genetics to drug discovery to model organisms to everything in between,” adds Gerard Schellenberg, professor of pathology and laboratory medicine (see sidebar on p. 40). “It makes for a really great critical mass.”

All told, there is enough concentrated scientific and organizational brainpower here to blow the plaques and tangles of Alzheimer’s and its neurodegenerative relatives out of the water. Just when that will happen, of course, remains to be seen.

“Sometimes in any given year progress seems incremental,” says Schellenberg. “I mean, we haven’t cured the disease. We don’t have a drug treatment yet. But we know so much more. When I started 30 years ago there were no drugs being tried. And then we had one drug approved. And now there are large numbers of drugs in trial, based on the knowledge that was generated by academic groups. So there’s been a payoff in knowledge in terms of getting stuff into clinical trials.”

Recently Trojanowski, Lee, and a number of their Penn colleagues put together a proposal for a series of Comprehensive Alzheimer’s Disease Centers around the country that would serve as kind of ramped-up CNDRs. Trojanowski envisions four or five of them (including one at Penn), each conducting “multidisciplinary patient-oriented clinical and basic science research” to improve understanding of and treatments for Alzheimer’s, Parkinson’s, FTLD, ALS, and vascular dementia “in the most cost-effective and efficient manner possible.” While each center would cost an estimated $20 million a year, Trojanowski and his colleagues argue forcefully that the results would lead to very significant savings in the cost of national healthcare.

“I’ve circulated that proposal to a number of donors and elected officials,” says Trojanowski. “I’ve met with [US Senator] Bob Casey and shared it with him. It’s something I’m willing to talk to anyone about and to push forward, but it’s so far unfunded.”
 


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

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SIDEBARS:

The Ethics of Alzheimer’s

Crossing the Valley of Death with Big Pharma

Genetic Dragnet


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