Unforgettable Breakthroughs in Alzheimer’s

Summer 2010

Back in the 1980s, it was becoming evident that Alzheimer’s disease was an imposing challenge whose weight on health and society was just beginning to be felt. As people began to live longer and the U.S. population began to age, more and more people were finding themselves on the receiving end of a diagnosis of this slow but deadly neurodegenerative disease. By the time President Ronald Reagan wrote a letter to his “fellow Americans” in November 1994 announcing his diagnosis of Alzheimer’s, the disease was already a household name — and the scientific community, keen on finding a cure, had just begun to congeal.

At Massachusetts General Hospital, one of the country’s first core teams of research scientists came together and cast a wide net of investigation, with early studies in genetics, biology and imaging. Today, fortified with a team exponentially larger, some of the most important breakthroughs in understanding Alzheimer’s have emerged from Mass General labs and clinics, positioning the hospital as a go-to source for research, diagnosis and treatment.

A diagnosis today is nothing short of frightening; there is no cure for the disease and doctors can only offer patients medications that slow Alzheimer’s progression. But some of the most revealing discoveries have emerged in the last five years right here at MGH while new studies are underway, holding promise for the future of individuals and families burdened with this diagnosis, and perhaps one day, a cure.

First, the genetics have been unraveled. Indeed, since the first genetic clues to the disease were uncovered here in 1987, Mass General has been the world epicenter of genetic discovery around Alzheimer’s. That year, a group led by Rudolph E. Tanzi, PhD, director of the Genetics and Aging Unit at MGH, identified the first gene implicated in early-onset Alzheimer’s disease — a subset of patients who get the disease in middle age — the amyloid precursor protein gene, or APP. It was a groundbreaking discovery: the APP gene causes a flood of beta-amyloid, the protein (also referred to as A-beta) that in large quantities forms plaques that take over the Alzheimer’s brain, effectively shutting down its neural network.

That protein, the physical manifestation of the disease on imaging scans, has continued to be the focus of most Alzheimer’s research to this day.

Dr. Tanzi and his colleagues also identified two additional genes in 1995. A fourth was identified at Duke University in 1993. For the next 10 years, most Alzheimer’s research and drug discovery was based on those four genes.

“Yet those genes only account for about 30 percent of cases, at most — there was so much more to be done,” says Dr. Tanzi.

His physician-colleagues at Mass General who treated Alzheimer’s patients knew that it can run in some families — although many cases are sporadic with no family pattern — so identifying other genes was imperative to moving towards a cure, he says.

The next research undertaking would be an expensive and risky one, not the kind that traditional funding mechanisms like the National Institutes of Health support. It would involve doing the world’s largest disease-specific genomic analysis ever undertaken. In 2005, a small group of wealthy individuals with personal and intellectual interests in finding a cure for Alzheimer’s came together to form Cure Alzheimer’s Fund. They believed that defining the genetics behind the disease was an essential step towards a cure and financially backed the project, a multi-million dollar commitment.

Today, as a result of the four-year so-called Alzheimer’s Genome Project, we now have a mostly comprehensive list of all the genes implicated in the disease: more than 100. The project analyzed genetic information from 1,700 Alzheimer’s families and more than 5,600 subjects. It identified the 10 most-important genes for drug discovery, some that play roles in advancing the disease and some that actually protect against it. The project also exposed the complexity of gene-to-gene interaction in Alzheimer’s: many of the genes involved play minor roles individually in determining whether a person will have Alzheimer’s, but small groups may collectively play important roles.

Other labs in his seven-lab unit and throughout the Mass General Institute for Neurodegenerative Disease, or MIND, of which Dr. Tanzi’s unit is a part, took his findings as they emerged and set off on trying to identify the right chemical compounds that might inhibit or exploit those mutations. And as with all medical science, there have been failures and successes along the way. A clinical trial for a potential vaccine, for instance, was terminated several years ago. But many small drug companies have been formed based on earlier discoveries in Dr. Tanzi’s unit, including Prana Biotechnology, which he founded and which produces a drug that moderates the level of beta-amyloid in the brain.

Today, with the near-comprehensive list in hand, the next step is to learn what all these genes do — whether they too spur floods of beta-amyloid or serve other functions altogether. “We have to parse through our treasure trove of data to understand these interactions between genes and figure out what the abnormalities in them actually do in the brain,” says Dr. Tanzi. Through partnerships with scientists at MGH and beyond, he says, “we’re starting to connect the dots” between the genes and clinical symptoms, pathological features, physical indicators of the imaged brain and in the spinal fluid — called “biomarkers” — as well as age of onset, level of risk and other factors.

The ultimate goal? Says Dr. Tanzi, “We want to be able to predict early in people’s lives whether they are at high risk for the disease and be able to prescribe preventative drugs so they won’t get it at all. I’m pretty confident that we’ll get there and that our work will serve as a model for other diseases.”

The attention to Alzheimer’s disease at Mass General is vast. A large web of centers and departments that interact with one another and focus on neurodegenerative diseases puts distinct emphasis on Alzheimer’s research and care. At MIND, in addition to Dr. Tanzi’s unit, the Alzheimer’s Disease Research Unit, directed by Bradley Hyman, MD, PhD, is comprised of a series of labs doing bench-to-bedside research. Dr. Hyman has a long history of breakthroughs in Alzheimer’s beginning with his discovery of the disease’s effects on the hippocampus, which plays a major role in long-term memory and spatial navigation. Other units at MIND focus on Parkinson’s, Huntington’s disease and ALS (Lou Gehrig’s disease), all of which share features with Alzheimer’s.

In addition, the Massachusetts Alzheimer’s Disease Research Center at MGH (ADRC) funds a spectrum of research initiatives. It was one of the first Alzheimer’s research centers established and funded by the National Institutes of Health when it was formed in 1984; now there are 30 such centers nationwide.

Mass General neurologist John Growdon, MD, ran it since its inception, and Dr. Hyman picked up the baton last year. In addition, the Memory and Movement Disorders Unit, headed by Dr. Growdon, which is part of the Department of Neurology, cares for hundreds of Alzheimer’s patients and provides access for patients to numerous clinical trials.

Thanks to that intricate research network, work on other neurodegenerative diseases at MGH is informing the study of Alzheimer’s. Scientists are now better able to distinguish between the neurodegenerative diseases like they never could before. Bradford Dickerson, MD, for instance, has pioneered the use of advanced imaging technologies to identify changes in the brains of living patients that may be useful for earlier diagnosis or monitoring of progression. He has applied these tools to differentiate between Alzheimer’s and other forms of dementia, including frontotemporal dementia. Capitalizing on the infrastructure already in place through the MGH ADRC and Memory Units, he founded the MGH Primary Progressive Aphasia Program and the MGH Frontotemporal Dementia Unit in 2007 to apply this knowledge to the diagnosis and care of patients with these related disorders.

That kind of cross-fertilization “was just what we were expecting and hoping for when we created MIND back in 1999 — and just look what kinds of advances it has nurtured,” says Anne Young, MD, PhD, chief of Neurology, scientific director of MIND and an expert in Parkinson’s and Huntington’s.

While a tremendous diversity of studies are underway here, finding ways to eradicate or modulate the production of beta-amyloid in the brain has been the target of much Alzheimer’s research in recent years, at Mass General and beyond. This interest has been based on the belief that if the beta-amyloid plaques are prevented from forming (which may also have a positive effect on the tangles inside the neurons that are seen in the disease) then individuals won’t develop symptoms. Likewise, if the plaques already exist and are reduced, symptoms of the disease would disappear.

As a result, most of the drugs in experimental trials today are aimed at reducing overproduction of the protein. In fact, a study out in the spring by Robert Moir, PhD, a member of Dr. Tanzi’s unit, showed that wiping out beta-amyloid in the brain actually has detrimental effects. “Beta-amyloid can be thought of much like cholesterol in the blood vessels: too much is not good for you and too little isn’t good for you either. It must exist in moderation,” says Dr. Moir.

For years, part of the challenge in understanding the biology of the plaques was actually being able to see them; they are microscopic. It was at MGH that a breakthrough in that area occurred, back in 2002. That year, a team of scientists at the University of Pittsburgh discovered a chemical compound that binds to the plaques that would highlight them on an imaging scan. The so-called Pittsburgh Compound was a tremendous achievement that took a decade to devise. That’s because scientists had to find a substance that would breach the blood-brain barrier, the membrane that protects the brain and prevents foreign substances from entering it. The same substance also
had to bind to the plaques for just long enough to view them on an imaging scan — and clear out of the brain before it did damage to it.

But the compound was useless without a highly powerful imaging machine that would highlight with precision the affected areas of the brain; traditional MRI and PET scanners don’t have the necessary resolution to show microscopic matter. Mass General had that equipment — a multi-photon confocal microscope — and a partnership between the two institutions was formed. It was the first time such a microscope was used on the human brain.

Dr. Hyman, together with MIND colleague Brian Bacskai, PhD, began imaging plaques in transgenic mice this way — mice who were given Alzheimer’s through the transfer of mutated genes. The result has been stunning visual records of the development of the disease in mouse brains over time, as well as the clearance of plaques through the use of drug therapies.

Now, clinical trials are underway at Mass General in humans using newer variations of the Pittsburgh Compound to view the disease at work in the brains of Alzheimer’s patients and monitor the reduction of beta-amyloid as patients receive certain medications.

“The improvements in imaging technology and resolution in the past five years have been astonishing and actually outpace our ability to understand what we’re seeing. We’ve had to catch up,” says Dr. Hyman. Much of this imaging work is centered around his partnership with the husband-wife team of Reisa Sperling, MD, MMSc, and Keith Johnson, MD, co-leaders of the MGH Alzheimer’s Disease Neuro-imaging Program affiliated with the Athinoula A. Martinos Center for Biomedical Imaging. Dr. Sperling, who also directs the MGH Center for Alzheimer’s Research and Treatment, is conducting imaging studies to detect the earliest brain changes in Alzheimer’s disease and to monitor response to new treatments in clinical trials.

One of the most important such findings is that many patients at the earliest stages of Alzheimer’s have heavy plaques but actually show few symptoms of the disease, suggesting that the disease in the brain starts long before symptoms appear. “This is really exciting because it means that there may be a place in the process that we can intervene and arrest the whole thing before people even show symptoms,” says Dr. Hyman.

For diagnostic purposes, however, imaging the brains of all patients suspected of having the disease simply isn’t feasible — it’s too expensive and time-consuming. So Dr. Hyman and his colleagues are trying to devise a diagnostic blood test. Today, no singular diagnostic test exists. Instead, doctors mainly rely on a series of memory tests, imaging scans and blood tests. A new potential test, now in its development stages by Mark Albers, MD, PhD, a MIND investigator, is based on a discovery that the loss of smell precedes the development of the memory symptoms of Alzheimer’s and the movement symptoms of Parkinson’s disease.

Meanwhile, additional research is underway parsing post-mortem brains of patients, exploring the differences in those with more and less severe forms of the disease, and — in tandem with Dr. Tanzi’s group — matching up that information with genetic data. And dozens more researchers are investigating new, uncharted waters in the disease.

Meanwhile, back in Dr. Tanzi’s lab, new and unexpected clues are emerging about the triggers that make beta-amyloid overproduce. One is that it is a critical player in the innate immune system and is useful for killing off infections. His team speculates that overproduction may be the result of an insult to the brain, like a traumatic brain injury, a stroke or an infection. “You can think of it like scar tissue after a sports injury, which forms to protect the injured joint but then stays there long after the injury is healed, leaving that joint far less mobile than it once was,” says Dr. Moir.

That would also make sense in the context of one of Dr. Hyman’s recent discoveries in 2008 that plaques can develop nearly overnight in mice. The study contradicted the accepted belief that plaques developed slowly over many years and implied that some kind of event initiates the process.

It’s also a clue that could lead to a new paradigm of thinking about — and potential treatments for — Alzheimer’s, because scientific knowledge about antibiotics in infection as well as brain trauma may now factor into understanding of the disease and, perhaps, one day, a cure.

A sampling of Alzheimer’s research studies underway at Mass General

• Using advanced imaging techniques, an investigation of the earliest changes in patients’ brains as Alzheimer’s begins
• Multiple investigations of novel therapies in mice to see which might protect the brain against Alzheimer’s
• A search for markers in patients’ blood that might precede the symptoms of dementia, for the purpose of diagnosing the disease and reassuring others with subtle or subjective symptoms that they do not have it
• The development of an imaging agent to distinguish Alzheimer’s from Lewy Body dementia and from Parkinson’s disease, which often have common symptoms
• Multiple clinical experimental thera-peutic trials for Alzheimer’s patients