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When neurologist Allan Levey arrived at Emory in 1991, there wasn’t much he could do for his patients with Alzheimer’s disease. He would explain the mysterious beta amyloid plaques in the brain that clogged synapses between neurons, and he could prepare patients and families for the next step in the patient’s deteriorating condition as well as take care of coexisting medical problems. But he watched too many patients simply waste away with agonizing slowness, bankrupting families financially and emotionally over the course of many years. And he became tired of it.
     “For so long, Alzheimer’s has been seen as a hopeless disease,” says Levey, chair of the Department of Neurology. “That is no longer the case. We are actually at a place in time where we can offer treatments that have been proven to work.”
     Levey collaborated on a landmark article published in the June 9, 2005, issue of the New England Journal of Medicine, concluding that the drug Aricept can delay the progression of Alzheimer’s for as long as three years if administered early in the course of the disease. “This is the most important clinical trial done to date in Alzheimer’s disease because it marks the very first time that we have delayed its onset,” Levey says. “It is a treatment that may work best for people at very high genetic risk. We showed an outcome that established that these people should be treated very early, and while we still have a long way to go, it was the first time we proved we could intervene in Alzheimer’s disease and make a difference.”

uring the past 15 years, Levey has helped link a vast network of Alzheimer’s research, clinical, and education projects at Emory. Having expanded exponentially in quantity and funding, these efforts form the crux of the Alzheimer’s Disease Research Center (ADRC), a recent designation granted by the National Institute of Aging (NIA). Along with the five-year, $7.4 million grant, the relevance of this designation is enormous, says Levey, who directs the center. The grant will attract more research dollars to Emory’s already formidable neurodegenerative disease efforts. The designation distinguishes Emory as one of the foremost research and clinical centers for Alzheimer’s disease in the country. The center also is supported by the Georgia Research Alliance, a private nonprofit partnership among statewide university and industry leaders and government, which will allow recruitment of an eminent scientist and investments in cutting-edge technologies and equipment.
     Boosted by basic science research in genetics and proteomics and advances in clinical care, research has yielded an explosion of new knowledge about Alzheimer’s. Technological advances in brain imaging and data management also have sped discoveries.
     Creighton Phelps, program director of the ADRCs at the NIA, says that only the very best university research programs receive this designation. “Emory was one of only two new centers funded by the NIA in 2005,” Phelps says, “and the process was intensely competitive.”
     Emory joins a network of 32 NIA centers nationwide dedicated to understanding the development, progression, diagnosis, and treatment of Alzheimer’s and related neurodegenerative diseases. The emphasis of the Emory center is to catch the disease as early as possible and halt its progress.
The importance of early intervention  
One tack Emory researchers are taking is to understand the role of mild cognitive impairment as a precursor to Alzheimer’s disease. “Not all people with mild cognitive impairment will develop Alzheimer’s disease, but it is a risk factor,” says Levey.
     For their clinical studies, the researchers are enrolling a combination of healthy volunteers and those with mild cognitive impairment from the patient population at Wesley Woods Center and Grady Memorial Hospital. “We can have the most impact if we can find ways to identify the disease early and intervene before too much damage is done,” Levey says.
     Despite the emphasis on early intervention to halt Alzheimer’s disease, early diagnosis is difficult because the disease shares so many symptoms with other neurologic disorders such as Parkinson’s disease, mini-strokes, and vascular disease. Enter Stuart Zola, director of the Yerkes National Primate Research Center and co-director of the Emory ADRC. Zola is applying his research in memory formation, consolidation, and retrieval to Alzheimer’s questions. One of the first scientists to develop a model of human amnesia in nonhuman primates that identified brain structures critical to memory function, he has helped scientists understand memory loss in humans resulting from head trauma and neurodegenerative diseases. His work with monkeys and its application to humans has resulted in the development of new diagnostic behavioral tools for diagnosing humans with mild cognitive impairment and with early-stage Alzheimer’s disease. It is crucial, according to Levey.
     “We now have a much better, more specific definition of Alzheimer’s disease, and we can diagnose it with much greater confidence and at much earlier stages than before.”
Not-so-sweet dreams  
Emory researchers are also busy on another front: exploring the role of sleep and neurologic dysfunction in Alzheimer’s. Donald Bliwise, Emory professor of neurology and director of the Program in Sleep, Aging, and Chronobiology, says many medical problems associated with aging—such as insulin resistance, hypertension, hypothyroidism, and low testosterone—may contribute to the progression of Alzheimer’s disease and cognitive decline.
     Sleep apnea, which affects 20% of the geriatric population, causes chronic oxygen deprivation (hypoxia) in the brain. Falling blood oxygen levels from periods of depressed breathing during sleep also stress the heart. A huge burst of autonomic sympathetic nervous system activity follows to awaken those in the throes of a sleep apnea episode. Apparently, once this nervous system sensitivity is set off, it’s hard to stop, and as a result, more stress hormones are released both day and night. Research has shown that sleep apnea causes both hypertension and insulin resistance. The cumulative effects of all these factors may play a role in neurologic decline, says Bliwise.

     “In our clinical studies, we’re finding that many Alzheimer’s patients have a long history of sleep apnea,” says Bliwise. “When you talk to patients and their caregivers in the clinic, you hear so much about snoring and gasping at night. The brain is a target organ for sleep apnea. There has been more of an emphasis on the cardiovascular effects of sleep apnea, but little attention has been paid to its relationship to Alzheimer’s disease. We’re charting new ground.”
     In fact, in addition to family history of the disease, identifying those with sleep apnea may be an important way to flag people at higher risk for Alzheimer’s, says Levey.
A visual diagnosis  
In the past, an Alzheimer’s diagnosis was little more than educated guesswork. Now, Emory radiologists are developing tools that offer a more definitive diagnosis via a picture of an Alzheimer’s brain.
     Mark Goodman, professor of radiology and director of the PET (positron emission tomography) Imaging Center at Emory, says PET images offer a look at brain function in living patients, allowing researchers to visually track the brain’s metabolism of glucose and oxygen. After many years of work, he has discovered a revolutionary pharmaceutical compound that when used with 3-D PET scans can highlight beta amyloid plaques in the living brain.
     “This agent gives us the ability to image the cognitive area of the brain—the frontal cortex—and see the beta amyloid plaques in a living person,” says Goodman. “Previously, we could see these plaques only after patients had died, too late to do any good. The ability to see and measure the severity of the plaques changes everything in Alzheimer’s diagnosis. It takes out the guesswork.”
     This compound can highlight plaques in several stages of development and is the first shown to be clinically practical. It is a radioactive molecule that has an affinity for beta amyloid plaques and chemically binds to them. When injected into the bloodstream, it has good delivery to the brain and allows for high-contrast images of amyloid plaques.
     “Our invention is the first that could be widely distributed to clinics and hospitals,” Goodman says. “It has a half-life of eight hours. The only other such agent known to work has a half-life of 20 minutes, making it impractical for use outside the lab.”
     The center is conducting a study using brain imaging and biomarker tests together with measures of memory, thinking, and daily functioning to see if an earlier diagnosis of Alzheimer’s can be made. The research participants include a control group, a group with mild cognitive impairment, and a group with Alzheimer’s disease. The two-year study should lead to a much faster process for better diagnostic tools and for testing medications that are targeted at the molecules that cause the disease.
Plucking proteins from plaques  
Genetics assistant professor Junmin Peng gestures proudly at a large wooden box taking up most of the hallway outside his lab. Inside is a new tool, the very latest technology in mass spectrometry, and Peng can’t wait to unpack it.
     “Just as a scale measures weight, the mass spectrometer measures the mass of very small molecules, like proteins,” Peng says. Matching a protein’s mass to the map of the human genome provides an accurate identification of the protein.
     “Without the database of the human genome, we can only measure the mass,” Peng says. “But with the human genome information, we can use the mass to identify the protein and quantify it.”

     Peng uses this tool to study the most basic proteins in beta amyloid plaques in brains of Alzheimer’s patients postmortem. Peng and neuropathologists at Emory use a laser scanning microscope to locate amyloid plaques and then pluck out a sample. The mass spectrometer measures the mass of the proteins comprising the plaques. Then, a powerful computing center in the Department of Human Genetics—32 processors in all—matches the mass to the proper protein, making a positive I.D.
     Proteomics, or the study of proteins, is opening new windows to understanding the development of Alzheimer’s disease, whether it’s caused by the absence of certain normal proteins in early Alzheimer’s patients or the buildup of too many.
     Sequencing of the human genome has propelled the field of proteomics, offering opportunities to apply it to diseases such as Alzheimer’s. “There was an explosion of information from the human genome map, which has a huge impact on our research,” Peng says. “It provides a framework like a whole database of the potential proteins present in humans. Mass spec-based proteomics is a young field, but it’s advancing very rapidly. We are on the cutting edge by applying it to Alzheimer’s and making a difference for real people—not just learning about molecules.”
It all comes back to the patient  
Past the fancy science and evolving high-tech inroads to a mysterious disease, making a difference for people is still the central focus of the Emory researchers and physicians. Every Monday, Levey spends the day at Wesley Woods, seeing inpatients and holding clinics for outpatients and their families. Many of his patients are involved in one of the many clinical studies that fall under the umbrella of the Emory ADRC.
     Caring for Alzheimer’s patients must also involve an entire family unit. “It is a familial disease with a strong genetic origin,” Levey says. “Family ties are very important, both as risk factors and in caring for patients.”
     Alzheimer’s disease takes a huge toll on caregivers. The need for emotional support and education is crucial to keeping patients out of nursing homes and in the best possible surroundings. “We recognize that the proper support must be in place for this to work,” Levey says. “Here at Wesley Woods, we’re providing that for families.”
     Beyond educating families, reaching out to the larger community is another goal. For example, the clinical center at Grady Memorial Hospital treats mostly African-American patients with Alzheimer’s, examining racial disparities in treatment and outcomes of the disease as well as cultural differences in how families cope. According to Levey, early dementia sometimes involves different factors in African-American patients, such as a higher prevalence of high blood pressure and diabetes.
     Data from all these clinical and scientific studies are collected and sent to the NIA annually. There the numbers are combined with those from all the other research centers around the country in nothing less than a full-scale national assault on what was once considered a hopeless disease. Now prevention and even a possible cure for Alzheimer’s disease are no longer just a dream. “We will do amazing things with this disease in my lifetime,” says Levey. “We’re so close I can practically taste it.”


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