Alzheimer’s disease is the most common form of dementia in the United States and currently affects one in eight older Americans. The most common signs and symptoms associated with Alzheimer’s disease include difficulties with cognition, memory and behavior and these deficits can progress such that patients ultimately require assistance with daily activities. As the population ages, the incidence of Alzheimer’s is projected to increase by 50 percent in Americans aged 65 and older by the year 2030. Current therapies have only been successful in temporarily delaying progression of symptoms, however no cure has been found. Given the prevalence of this disease as well as the increasing health costs associated with medical and home care for these patients, novel clinical therapies are urgently needed. The exact cause and mechanisms of Alzheimer’s are unknown; however two abnormal structures are hallmarks of the disease: extracellular protein fragments known as amyloid-beta (β) plaques and intracellular tangles of the protein tau. Impaired metabolism of plaques and the accumulation of amyloid-β and tau lead to neuronal degeneration, which are thought to be the cause of Alzheimer’s disease’s clinical symptoms.
Alzheimer’s appears to trigger an inflammatory response in the brain, which leads to the activation of microglial cells, a type of macrophage specific to the central nervous system. Microglia has been shown to accumulate at amyloid deposits and release mediators of the inflammatory response. This inflammatory response has been associated with both neurodegeneration and neuronal survival with tissue repair. Many clinical trials to date studying Alzheimer’s have targeted this inflammatory response. The clinical success of Alzheimer’s drugs has been limited by the protective nature of the blood brain barrier, known as BBB, despite the fact that the BBB is frequently disturbed in Alzheimer’s patients.
The departments of radiation oncology and neurosurgery at Beaumont have embarked upon a novel approach to this clinical problem.
Ionizing radiation therapy, known as RT, has been used therapeutically in both malignant and benign conditions in multiple organ sites, including symptomatic amyloidosis. RT has been shown to improve the clinical appearance and associated symptoms of amyloid deposits in areas other than the brain. Applying the external beam of ionizing radiation for the treatment of Alzheimer’s associated amyloid-β plaques; the research team has applied the use of modest doses of RT as a potential novel treatment approach for Alzheimer’s disease. Initial findings using a transgenic murine model of early-onset Alzheimer’s demonstrated a 50 to 80 percent reduction in amyloid-β plaques in both the hippocampus and cortex of aged subjects following modest-dose RT to the brain using a diverse range of radiation dose and time parameters. A reduction in plaque size was also evident. Both single dose radiation treatments and multiple dose treatments given daily over one to two weeks, defined as clinically acceptable for healthy brain tissue, were found effective.
This experimental study used a hemi-brain treatment technique, which allows for comparison between irradiated and non-irradiated brain within individual subjects that exhibit different amyloid- β plaque burdens. The team has hypothesized that modest doses of RT are associated with a local inflammatory response, which ultimately leads to a reduction in the burden of amyloid-β plaques. This hypothesis is in keeping with the lack of efficacy of anti-inflammatory therapy in Alzheimer’s patients in clinical trials, as the inflammatory response may, in fact, be a key to reducing amyloid-β burden. Alternatively, the reduction in plaque burden could be a secondary result of radiation-mediated repair responses. Beaumont’s ongoing experiments are addressing whether a reduction in plaque burden is associated with cognitive improvements in symptomatic animals.
Additionally, it is planned to further characterize the optimal RT dose and timing, and determine whether RT given in pre-symptomatic subjects prevents plaque formation and possible development of Alzheimer’s entirely. Given the translational nature of the research, the ultimate objective is to determine whether this novel approach will have clinical application for Alzheimer’s disease patients. To date, this work has been supported by the department of Radiation Oncology and Michigan Head and Spine Institute, PC
MHSI Neurosurgeon, Daniel Michael, M.D., Ph.D.(pictured above), listed as part of the Alzheimer's disease research team along with Brian Marples, M.D., George Wilson, Ph.D., James Fontanesi, M.D., and Mackenzie McGee, M.D.