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Mary S. Easton Center for Alzheimer's Disease Research at UCLA Welcomes New Director
"We need to be better internists. We have to look at the whole picture, the whole patient."
By: UCLA Department of Neurology, "Partner in Discovery" - Spring 2014 Issue
Photo: Dale E. Bredesen, M.D.
Augustus Rose Professor of Neurology
Center Director, Mary S. Easton Center
Director of Alzheimer's Disease Program
Director of Neurodegenerative Disease Research
David Geffen School of Medicine at UCLA
In January, the UCLA Department of Neurology and the Mary S. Easton Center welcomed a new Director, Dr. Dale Bredesen. A world-renowned scientist and expert in Alzheimer’s disease and other neurodegenerative disorders, Dr. Bredesen is the Director of the Easton Center and the Alzheimer’s Disease Program in the Department of Neurology. He is also the Augustus Rose Professor of Neurology and Director of Neurodegenerative Disease Research at the David Geffen School of Medicine at UCLA.
For Dr. Bredesen, coming to UCLA is a homecoming. He graduated from the California Institute of Technology (Caltech), where his work focused on the “machinery of the brain”-essentially, how it operates. He then completed his medical degree at Duke and residency and fellowship at UC San Francisco, where he was Chief Resident and studied with Nobel laureate Dr. Stanley Prusiner. Dr. Bredesen then served on the Department of Neurology faculty at UCLA for five years before departing in 1994 to lead the Program on Aging at the Burnham Institute in San Diego. In 1998, Dr. Bredesen became the founding President and CEO of the Buck Institute for Research on Aging in Marin County, California.
An international expert on neurodegenerative disease and, in particular, Alzheimer's disease, Dr. Bredesen had a distinguished career in this field, to which his numerous national and international lectures and awards are a testament. He now brings this work to UCLA, with the expressed intent of moving his research into the clinic and improving the number of treatments that clinicians have to offer patients and their families dealing with neurodegenerative diseases. Dr. Bredesen has spent the last 14 years engaged in basic science research to better understand the biological balances and imbalances that lead to the progressive synapse, cell loss, and memory impairment in Alzheimer’s disease, with a special focus on developing improved treatments that can slow the disease and reverse cognitive decline.
"I came back to UCLA for two reasons," Dr. Bredesen said. "First, the school has a stellar history in neuroscience, with clinical relevance in translational research; and second, because of the Easton Center, which offers patients access to both treatment and research, in addition to a strong patient support system," said Bredesen. "There is a dire need for a truly effective treatment for Alzheimer’s disease, and no other institution is more prepared to develop this than UCLA. The basic neuroscience, the Easton Center, the clinical research and trials, the superb faculty, the innovative spirit, and the wonderful community relationship all make me enthusiastic to return to UCLA."
Dr. Bredesen's goal is to produce the first set of truly effective therapeutics for Alzheimer's disease. "We need to be better internists. We have to look at the whole picture, the whole patient," he explained. "We need to bring in molecular biology, for example; look at the patient's hormones; the types of food he or she eats; their levels of sleep; their energy and vitamin levels. Just as each brain is unique, so is the way each body deals with inflammation."
"It has been 108 years since the discovery of Alzheimer's disease. Our challenge is to break the dogma and reverse the hopelessness-to develop real treatments and cures. We need to get people to come in at the very beginning to get treatment early-on," said Dr. Bredesen.
"Thanks to combined training in basic science and clinical research, Dr. Bredesen is in a unique position to bring together many dedicated and experienced UCLA faculty who have interests in this vitally important set of disorders, which have reached epidemic proportions throughout the world," said Dr. John C. Mazziotta, Chairman of the UCLA Department of Neurology.
Please join the Department of Neurology in welcoming Dr. Dale Bredesen back to UCLA. His presence and leadership will bring exciting opportunities to the University.
New Study of Vitamin E as a Therapy for Alzheimer’s Disease Yields Mixed Results
By: Joshua Grill, Ph.D.
The results of the first major clinical trial of vitamin E as a potential treatment for Alzheimer's disease were published in 1997. Since then, trials of vitamin E have varied in the doses tested, the length of studies, and the disease severity of the populations enrolled and have produced inconsistent findings. Combined with concerns about safety risks related to high doses of vitamin E, making clinical recommendations can be challenging. A new study published by Dysken and colleagues in the Journal of the American Medical Association (JAMA) adds to the mixed literature on whether vitamin E is an effective therapy for Alzheimer’s disease.
In the study, men receiving care for their Alzheimer's disease at Veterans Affairs hospitals who had mild-to-moderate Alzheimer’s disease, defined as a score of 12-26 on the Mini-Mental State Exam, received 2000 International Units per day (IU/d) of vitamin E, 20 mg of memantine (Namenda®) per day, both treatments, or placebo for an average of 2.27 years. All participants were receiving acetylcholinesterase inhibitor therapy (donepezil [Aricept®], galantamine [Razadyne®], or rivastigmine [Exelon®]) at baseline.
Participants randomly assigned to vitamin E showed reduced decline over time, compared to those assigned to placebo, in their ability to perform daily living activities and this difference was statistically significant. No benefits were observed for the group who received vitamin E and memantine or the group that received only memantine. No benefits were observed for any group on measures of memory or other forms of cognition.
This study suggests that vitamin E may slow functional decline in Alzheimer’s disease. Equally important is the finding that the high dose of vitamin E did not increase the risk of death or other adverse events, relative to placebo. This is in contrast to the results of other previous studies, which warn against vitamin E treatment at doses higher than 400 IU/d. It is challenging to determine whether these new results overcome the long-standing safety concerns related to higher doses of vitamin E. Perhaps more importantly, it remains critical that patients and caregivers discuss these and other findings with a clinician before beginning or changing their daily dose of vitamin E or any other medicine or supplement.
It should be no surprise that memantine failed to improve functional or cognitive performance in these mild-to-moderate Alzheimer’s disease patients. Memantine is approved only in moderate-to-severe disease because clinical trials have demonstrated efficacy only in these patients. Particularly vexing, however, is the observation that vitamin E in combination with memantine was not effective. While this may suggest potential interactions among therapies that remove benefits, mechanisms for such actions are unknown. Thus, the enthusiasm for the overall study results must be tempered.
Dysken MW, et al. JAMA. 2013;311(1):33-44.
Un nuevo estudio sobre la vitamina E como terapia para la enfermedad de Alzheimer genera resultados mesclados
Escrito por: Raquel Tenorio, Vanessa Garcia, and Joshua Grill, Ph.D.
Los resultados del primer gran estudio clínico de vitamina E como un tratamiento potencial para la enfermedad de Alzheimer fueron publicados en 1997. Desde entonces, estudios médicos de vitamina E han variado en las dosis probadas, la duración del estudio, y la severidad de la enfermedad de la población inscrita. Esta variedad ha producido resultados inconsistentes. Combinando esto con las preocupaciones de riesgos a la seguridad relacionados a la alta dosis de vitamina E, dar recomendaciones clínicas pueden ser difícil. Un nuevo estudio publicado por Dysken y colegas en el diario “Journal of the American Medical Association” (JAMA) añide a la literatura mesclada de si la vitamina E es una terapia efectiva para la enfermedad de Alzheimer.
En el estudio, hombres que estaban recibiendo cuidado para su enfermedad de Alzheimer en el hospital de Asuntos de Veteranos y que tienen un nivel leve a moderado de la enfermedad de Alzheimer, definido por una marca de 12-26 en un examen mental “Mini- Mental State Exam”, recibieron 2000 unidades internacionales por día (IU/d) de vitamina E, 20mg por día de memantine (Namenda ®), ambos tratamientos, o placebo por un promedio de 2.27 años. Todos los participantes recibieron terapia de inhibidores de la acetilcolinesterasa (donepezil [Aricept®], galantamine [Razadyne ®], o rivastigmine [Exelon®] al inicio del estudio.
Los participantes que fueron asignados al azar a la vitamina E mostraron menos disminución con el tiempo, comparados a aquellos asignados a el placebo, en sus habilidad de ejercer actividades de vida diaria y esta diferencia fue estadísticamente significante. Ningún beneficio fue observado en el grupo que recibió vitamina E y memantine o en el grupo que recibió solamente memantine. Ningún beneficio fue observado en cualquiera de los grupos en medidas de memoria o de otras formas de cognición.
Este estudio sugiere que la vitamina E puede alentar el deterioro funcional en la enfermedad de Alzheimer. Igual de importantes son los descubrimientos que muestran que la dosis más alta de vitamina E no elevan el riesgo de muerte, u otros eventos adversos, al compararse con el placebo. Esto es en contraste a los resultados de otros estudios previos, que le advierten contra el tratamiento de la vitamina E en dosis mayores de 400IU/d. Es difícil determinar si estos nuevos resultados superaran las preocupaciones de seguridad anteriores relacionadas a la dosis alta de la vitamina E. Quizás es más importante que siga siendo crítico que los pacientes y los cuidadores hablen de estos y otros descubrimientos con un médico antes de comenzar o cambiar su dosis diaria de vitamina E o cualquier otro medicamento o suplemento.
No debe ser ninguna sorpresa que memantine no logró mejorar el rendimiento funcional o cognitivo en estos pacientes con un nivel leve a moderado de la enfermedad de Alzheimer. Memantine es aprobada sólo en la enfermedad de moderada a grave porque los ensayos clínicos han demostrado la eficacia sólo en estos pacientes. Particularmente irritante, es la observación de que la vitamina E en combinación con memantine no fue efectiva. Mientras que esto puede sugerir posibles interacciones entre las terapias que eliminen los beneficios, mecanismos de este tipo de interacciones son desconocidos. Por lo tanto, el entusiasmo por los resultados generales del estudio deben ser atemperados.
Latest Major Industry Trial Results Announced
On January 23, two papers were published in the New England Journal of Medicine describing the latest Phase 3 clinical trial results for Alzheimer’s disease. The papers described the trials of two immunotherapies in development for Alzheimer’s disease; bapineuzumab and solanezumab. Both drugs are monoclonal antibodies against the amyloid β (Aβ) protein—the protein that accumulates in the brain of Alzheimer’s disease patients. Both sets of studies failed to demonstrate drug efficacy sufficient to achieve FDA approval. Both sets of studies did, however, provide important findings that represent steps toward improved scientific understanding of disease and, hopefully, improved treatments.
The efficacy results of the bapineuzumab trials were clear; the drug did not slow the cognitive or functional decline associated with disease. The drug was also associated with an important safety profile; depending on the dose of drug and patients’ APOE ε4 genotype, 4% to 15% of patients experienced what is referred to as Amyloid-Related Imaging Abnormalities (ARIA), including edema (leakage) and microhemorrhages (bleeding) in the brain, believed to be caused by the drug targeting and removing brain Aβ. In a substudy of the larger trial, a significant difference in brain Aβ levels (measured with amyloid PET scans) was observed between those receiving bapineuzumab and placebo. But this effect was limited to APOE ε4 carriers and reached significance because the placebo group increased in Aβ levels, while the treatment group remained stable; not because the treatment significantly reduced Aβ. Lastly, bapineuzumab significantly reduced measures phospho-tau (a marker of the neurofibrillary tangles in the Alzheimer’s brain) in APOE ε4 carriers but only did so at higher doses in the non-carriers.
For solanezumab, the results were different. Solanezumab did not demonstrate statistically significant reduced decline in cognitive or functional outcomes in either trial. But there were some intriguing and potentially promising results. First, solanezumab had a promising safety profile. Less than 1% of participants receiving solanezumab experienced ARIA, not different from the rate in placebo. Second, planned sub-analyses suggested that solanezumab may have slowed cognitive and functional decline in the mild (but not the moderate) participants. Biomarker tests showed that solanezumab treatment increased Aβ in the blood and the cerebrospinal fluid, perhaps because the drug helped move Aβ out of the brain.
While at first blush, both reports represent another disappointment in the pursuit of better treatments for Alzheimer’s disease, it must be noted that these are important steps. Collectively, these findings suggest that drugs targeting Aβ may also have downstream benefit, but that early intervention may be necessary to optimize success. The Easton Center is participating in a new Phase III study examining whether the signal of efficacy observed in the mild patients treated with solanezumab can be replicated. If it is, this could be enough for solanezumab to achieve FDA approval. Moreover, the notion that early intervention may enhance the likelihood of success is being tested in several new studies at UCLA and worldwide. This includes the Anti-Amyloid in Asymptomatic AD (A4) trial of cognitively normal 65-year-olds and the Dominantly Inherited Alzheimer’s Network – Treatment Unit (DIAN TU) of persons at risk for the purely genetic familial form of Alzheimer’s. All of these studies will need large numbers of volunteers to be successful.
Clinical Research Opportunities
If you would like to advance Alzheimer's disease research, please consider participating at the Easton Center. Below are two current trials. For a complete list of enrolling studies, visit our website at www.eastonad.ucla.edu.
Solanezumab Versus Placebo (EXPEDITION 3) in Mild Alzheimer's Disease:
The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) Study: In general, you may be eligible to join the A4 Study if you:
In general, you may be eligible to join the A4 Study if you: