Major Alzheimer’s Risk Gene Causes Alterations in Shapes of Brain Protein Deposits

Newswise — Researchers at Mount Sinai School of Medicine have used a newly discovered class of biomarkers to investigate the possibility that the shape of brain protein deposits is different in people with Alzheimer’s who have the highest-risk gene type than in those with the condition who have a neutral risk gene type. The study is being presented July 14 at the 2010 Alzheimer’s Association International Conference on Alzheimer's Disease in Honolulu, Hawaii.

Sam Gandy, MD, PhD, the Mount Sinai Professor in Alzheimer’s Disease Research, Professor of Neurology and Psychiatry, and Associate Director of the Alzheimer’s Disease Research Center at Mount Sinai School of Medicine, led the study. Mount Sinai labs led by Patrick R. Hof, MD, Regenstreif Professor of Neuroscience and Vice-Chair for Translational Neuroscience of the Department of Neuroscience and Dara L. Dickstein, PhD, Assistant Professor, Neuroscience also collaborated on the study.

Apolipoprotein E (APOE) is a gene containing instructions needed to make a protein that helps carry cholesterol in the bloodstream. The APOE gene, which comes in several different forms, is related to increased risk of developing Alzheimer’s disease. People with APOE ε4/ε4 gene type have the highest risk of developing the disease and people with APOE ε3/ε3 have a neutral risk. Discovering the important mechanisms underlying how APOE ε4/ε4 increases Alzheimer’s risk has been one of the most vexing mysteries facing Alzheimer’s researchers for over a decade.

Luminescent conjugated oligothiophenes (LCOs) or luminescent conjugated polymers (LCPs), the newly discovered class of biomarkers, can stick to protein structures in the body and emit colors reflecting the different shapes or forms of the proteins. Among other uses, LCPs/LCOs are currently being employed in test tubes, animal models, and autopsied Alzheimer’s brains to study the structure of proteins deposits caused by the disease. The new markers bind to the two well-established hallmarks of Alzheimer’s – beta amyloid plaques and tau tangles – and glow different colors depending on which forms of the deposits they “stick” to (e.g., plaques often “glow” orange, while tangles “glow” yellowish green).

In the study, frozen brain sections from people who died with Alzheimer’s were stained using two LCPs/LCOs: pentamer formyl thiophene acetic acid (pFTAA) and polythiophene acetic acid (PTAA). Using PTAA, the researchers observed that Alzheimer patients with APOE ε4/ε4 gene type had core and cerebrovascular amyloid of different shapes, while in people with APOE ε3/ε3, the two amyloid structures had the same shape. Using pFTAA revealed that tau tangle densities in ε4/ε4 Alzheimer patients that were apparently greater than those with ε3/ε3.

“The findings support our hypothesis that APOE genotype changes amyloid structure,” Dr. Gandy said. “This is important because the different shapes might respond differently to treatments that attempt to clear amyloid deposits from the brain. We already know, for example, that APOE ε4/ε4 patients respond less well to anti-amyloid antibody with bapineuzumab.”

LCOs/LCPs were pioneered by Peter Nilsson, PhD, Assistant Professor of the Department of Chemistry, Linköping University, Sweden. The study also involved collaborating teams from Charité – Universitätsmedizin Berlin, Germany, led by Frank Heppner MD, Director of the Department of Neuropathology and Washington University, St Louis, led by David Holtzman MD, Professor and Chair of Neurology.

About The Mount Sinai Medical CenterThe Mount Sinai Medical Center encompasses both The Mount Sinai Hospital and Mount Sinai School of Medicine. Established in 1968, Mount Sinai School of Medicine is one of few medical schools embedded in a hospital in the United States. It has more than 3,400 faculty in 32 departments and 15 institutes, and ranks among the top 20 medical schools both in National Institute of Health funding and by U.S. News & World Report. The school received the 2009 Spencer Foreman Award for Outstanding Community Service from the Association of American Medical Colleges. The Mount Sinai Hospital, founded in 1852, is a 1,171-bed tertiary- and quaternary-care teaching facility and one of the nation’s oldest, largest and most-respected voluntary hospitals. In 2009, U.S. News & World Report ranked The Mount Sinai Hospital among the nation’s top 20 hospitals based on reputation, patient safety, and other patient-care factors. Nearly 60,000 people were treated at Mount Sinai as inpatients last year, and approximately 530,000 outpatient visits took place. For more information, visit www.mountsinai.org. Follow us on Twitter @mountsinainyc.

About AAICADThe Alzheimer’s Association International Conference on Alzheimer's Disease (AAICAD) brings together 4,000 researchers from around the world to report and discuss groundbreaking research and information on the cause, diagnosis, treatment and prevention of Alzheimer’s disease and related disorders. As a part of the Alzheimer’s Association’s research program, AAICAD serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.

About the Alzheimer’s AssociationThe Alzheimer’s Association is the leading voluntary health organization in Alzheimer care, support and research. Our mission is to eliminate Alzheimer’s through the advancement of research, to provide and enhance care and support for all affected, and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer’s. Visit www.alz.org or call 800-272-3900.