From the desk of
Bruce L. Miller, MD
Medical Director, JDFAF

The Relentless Advance Against Alzheimer’s Disease

The relentless advance against Alzheimer’s disease (AD) and related disorders continues, despite significant challenges related to the world’s economic recession leading to serious cutbacks in funding for research. Through your generous donations, The John Douglas French Alzheimer's Foundation (JDFAF) has maintained constant support for fellows and Assistant Professors across the State of California — young scientists who are making important breakthroughs in the understanding of degenerative brain disease. Some of the most significant discoveries made in the past several years have come from JDFAF scholars who are probing AD, frontotemporal degeneration (FTD) and Parkinson’s-related cognitive syndromes.

In this science update I want to touch on the status of important clinical trials for AD and FTD, and describe new research efforts from JDFAF fellows related to neuroimaging and diagnosis. Also, I note exciting research designed to develop cellular models of these disorders in the test tube, using a new technology called iPS where skin cells from patients are used to generate and grow neurons.

Clinical Trials: In 2010 and early 2011 we are going to see the completion of important phase-III pharmaceutical trials that are designed to slow (or possibly stop) the progression of AD. Although we currently have mildly effective compounds designed to treat symptoms in AD, no disease-modifying therapies yet exist. There is strong evidence from a variety of models that the overproduction or poor clearance of an amyloid protein called A-b42 is an important factor in the development of AD. This protein is the target of a wide-range of pharmaceutical companies. The approach that has been brought into clinical studies ranges from the use of medications that slow the production of A-b42 to stimulating the immune system to increase the clearance of A-b42. The immunological approaches have been highly targeted, such as giving antibodies that specifically bind to A-b42 or stimulating the patient’s own immune system via vaccination to generate an immune reaction against A-b42. Another promising approach utilizes a compound called Dimebon that works by stimulating the brain’s mitochondria, the energy-generating part of the cell. These exciting clinical trials are going on across California and JDFAF Board member Dr. Jeffrey Cummings at UCLA, and JDFAF Distinguished Scholar Dr. Adam Boxer at UCSF are involved in testing these new approaches to AD. Simultaneously, JDFAF scholars at UCLA (Dr. Ed Teng), and USC (Drs. Ralf Langen, Wang Lu and Tobias Ulmer) are exploring new ways to treat AD at a molecular level.

Many people believe that the abnormal aggregation of the protein tau is as important in AD as Ab42. Furthermore, tau is clearly the central problem in other neurodegenerative conditions including FTD, progressive supranuclear palsy and corticobasal degeneration. Dr. Boxer will begin a trial in early 2010 with a new compound called AL-108 that is designed to prevent the aggregation of tau. In his first studies, Dr. Boxer will begin trials designed to slow down the course in FTD, progressive supranuclear palsy and corticobasal degeneration. If efficacy is shown with these disorders, Dr. Boxer will be involved with organizing trials against AD.  

Neuroimaging – Improving Diagnosis: As scientists develop disease specific therapies for neurodegenerative conditions, it becomes ever more important to improve diagnosis. JDFAF scholars at UCSF and UCLA have pioneered two different approaches to improving diagnosis using neuroimaging. Dr. William Seeley at UCSF has used structural and functional MRI to track the breakdown of functional circuits within the brain. In a groundbreaking study recently published in the prestigious journal Neuron, Dr. Seeley showed that AD and FTD cause degeneration in distinctive and specific circuits within the brain. In the case of AD the circuit is posterior, while in FTD the circuit rests in the anterior (frontal) parts of the brain. This exciting and non-invasive approach shows great promise for detecting the earliest changes associated with AD, FTD and other neurodegenerative conditions, and for following the effects of new treatments. Dr. Gil Rabinovici, a previous JDFAF fellow has worked with a compound called PIB that binds to Ab-42 and can be imaged with PET. His work is demonstrating the powerful role that this type of imaging is likely to play in early diagnosis of AD. In parallel research at UCLA, Dr. Gary Small has elucidated the value of a compound called FDDNP for imaging both Ab-42 and tau. Your funding to the French Foundation has made these pioneering studies possible.

iPS – From Skin Cell to Neuron: Dr. Shinya Yamanaka, a pioneering Japanese scientist (also at UCSF) developed a new technique that allows scientists to take a tiny piece of skin and convert this into a pluripotent stem cell. Subsequently the stem cell can be converted in a specialized cell such as a liver cell, heart cell or neuron. I have had the privilege of working with scientists who are taking skin cells from my patients with neurodegenerative conditions and in less than six months have already begun to have tissue cultures filled with neurons. Dr. Eric Wexler has proposed similar work at UCLA. We are all hopeful that these neurons will prove to be powerful for studying AD, FTD and other neurodegenerative conditions in cell culture and will help with the effective screening of different medications.

These remain exciting, but challenging times for research, yet never has research been more important. We need to break this terrible epidemic of age-related neurodegeneration. Your support for our foundation is making that a real hope for the coming decade.  

If you have questions about any research we are doing, please feel free to contact me through this website:

                                                                     www.jdfaf.org

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