Alzheimer’s Research from Molecular to Mundane

At Georgetown University Medical Center, scientists and physicians, at the bench and at the bedside, are studying all levels of Alzheimer’s disease and its possible triggers and potential therapies, from the molecular to the mundane. What cellular and basic biological changes occur, when, and why? What about life events such as head injuries, duration of education and family history? What is the impact of lifestyle choices such as smoking, drinking, diet, and exercise?

Alzheimer’s mirrors the nation’s health care crisis: an aging population, facing terminal, long-lasting, care-intensive illness with steeply escalating costs, amid a roller-coaster economy, in a health care system more adept at providing comfort than cures.

More than 5 million Americans suffer from Alzheimer’s disease, the sixth leading cause of death and the only fatal disease in our nation that is getting worse, not better. The costs of caring for patients during their deadly downward spiral is more than $100 billion annually, making it the third most costly illness after heart disease and cancer.

The need for therapies and cures is urgent. Patients appear lost within themselves, unreachable in their own lives, where the deterioration creeps into every corner. What limited treatments are available make sufferers more comfortable. Yet they are used only after the disease, deep-rooted and full-fledged, already has done obvious damage.

“The research occurring at GUMC is designed to understand what causes disease onset and progression so that early intervention – including conventional and novel therapies – can have the greatest impact,” said Howard J. Federoff, MD, PhD, Executive Vice President for Health Sciences and Executive Dean for the School of Medicine. “As the population ages, the need to fully understand the pathogenesis of Alzheimer’s is vitally important to our nation, our health care system, and the economy.”

A $3.1 million National Institutes of Health grant Federoff received in 2008 is driving GUMC researchers to develop methods to detect the disease earlier. The department of neurology has four renewed NIH training grants, the highest number of neurology training grants of any medical university in the United States.

Already underway at GUMC are the first-ever neurosurgical and gene therapy focused Alzheimer’s clinical trials in the nation. The Memory Disorders Program, led by R. Scott Turner, MD, PhD, is among the nation’s most active in the research and testing of new drugs and vaccines for Alzheimer’s. In partnership with MedStar’s Georgetown University Hospital, the program provides care to more than 1,500 patients. The program has also begun recruiting volunteers for a national gene therapy trial for patients with dementia due to Alzheimer’s disease.

Researchers at GUMC already have made some remarkable neurological discoveries that are transforming glimmers of hope into beacons of possibility. For example, the key to repairing the cell damage that causes profound alteration in patients with Alzheimer’s, Parkinson’s disease and traumatic brain injury -- as well as with spinal cord injuries and multiple sclerosis -- lies in the similarities in how cells live or die in these diseases. Blood tests can show patients’ sensitivities to these diseases, an early warning to enable physicians to reduce the damage before it spreads. And, some drugs for Alzheimer’s also reduce the harm caused by traumatic brain injury in animals and so could stem the long-term and continuing decline that usually follows these injuries.

Ongoing research on Alzheimer’s at the Medical Center includes:

Federoff’s focus on gene therapy and neurodegenerative diseases including Alzheimer’s seeks to discover how pathogenic processes affect cells, then use those findings to develop preclinical therapeutic strategies, and then move the most promising therapies to early stage clinical trials. He is also working to develop an amplicon-based vaccination for Alzheimer’s.

Turner’s research includes studies of passive immunization of mice; the role of DHA, a type of omega-3 fatty acid found in fish and walnuts, and its effect on the production and protection of brain cells against the harmful effects of amyloid protein that would slow the progression of memory loss; the regulation of the amyloid precursor protein (APP) breakdown that could lead to new therapeutic targets including a potential gene-therapy approach; and a trial to evaluate the impact of resveratrol treatment, a compound that promotes neuronal survival, on AD biomarkers and on patients with mild to moderate Alzheimer’s disease.

G. William Rebeck, PhD, associate professor of neuroscience and a member of the Center for Neural Injury and Recovery at Georgetown, has found that the strongest genetic risk factor for Alzheimer’s is APOE. Known to encode a protein in cholesterol transport to the blood and the brain, which can increase the accumulation of plaques in the brain, its function in the brain is still not well understood. One form of the gene-APOE epsilon 4-increases vulnerability to sporadic Alzheimer’s. Rebeck found that a pair of APOE ε4 genes appears to signal an almost certain victim of Alzheimer’s, helping to explain the nature of family history. He and his lab of post-doctoral fellows, graduate students, and undergraduates are examining ways of interfering with this process to diminish the negative effects of the gene and high cholesterol.

Mark P. Burns, PhD, assistant professor, department of neuroscience, found that cholesterol lowering therapies, such as statin drugs, more than cut in half the production of toxic proteins that hallmark AD. He and his researchers also are investigating the mechanism behind the observations that head injury can increase the risk of Alzheimer’s.

Hyang-Sook Hoe, PhD, assistant professor, department of neuroscience, is investigating how the APOE protein affects the formation and stability of synapses in the brain. She has identified mechanisms for reversing the neuronal deficits seen in individuals with APOE ε4, and is pursuing new therapeutic approaches to Alzheimer’s in mouse models.

Tim R. Mhyre, PhD, assistant professor, department of neuroscience, studies alterations in peripheral immune cells in Alzheimer’s. His team is working to develop clinical biomarkers to help diagnose and stage the disease and perhaps help in the discovery of curative drugs. The researchers examine how genes, biological molecules, and different proteins in blood influence disease risk. One goal is to create an archive of high quality human samples, an important resource for future work on disease processes--injury, repair, and therapies.

Click here to read more about GUMC's research on Alzheimer's disease.

By Victoria Churchville, GUMC Science Writer