Five Questions With: Dr. Brian Ott

"We hope to see at least a 30 percent reduction in decline on tests of memory and thinking over the three years."

Brian R. Ott is professor in the Department of Neurology at the Warren Alpert Medical School of Brown University and directs the Alzheimer’s Disease & Memory Disorders Center at Rhode Island Hospital, the largest memory diagnostic and treatment center in Rhode Island and regional referral center for southern New England. He is directing a new study, named Anti-Amyloid in Asymptomatic Alzheimer’s (or A4), of people who are at risk for Alzheimer’s disease but who have yet to show any symptoms. Anyone interested in more information on the study may contact Kerstin Calia at 401-444-9861 or kcalia@lifespan.org.

PBN: The asymptomatic Alzheimer’s disease study at Rhode Island Hospital is part of a national project. How large is the project, and how long has it been going on?
OTT:
The Anti-Amyloid in Asymptomatic Alzheimer’s study (A4 study) represents a huge undertaking. It is a national effort sponsored in part by the National Institutes of Health, along with the Eli Lilly pharmaceutical company. The study seeks to administer intravenous antibodies against amyloid protein on a monthly basis to 1,000 cognitively healthy older volunteers over three years; half will be assigned placebo infusions to compare the effect of the active treatment intervention. It is estimated that for the age group being targeted in the study (65 to 85 years), only 1 in every 3 people will have evidence of elevated amyloid on their PET scan.

PBN: Has similar research been done yet in other countries attempting to limit the development of plaque in the brain caused by these proteins?
OTT:
This is the first study of its kind to examine the possibility that a drug aimed at reducing amyloid accumulation in the brain could slow Alzheimer-related damage in the brain and delay symptoms of memory loss in individuals who have evidence of amyloid accumulation in their brain but who do not yet show symptoms of Alzheimer’s. A previous international study of the antibody being used in A4, that included people with already established Alzheimer dementia, showed no significant results overall, but secondary analyses of those with milder degrees of memory loss appeared to show a benefit in terms of slowing memory loss. This evidence has sparked hope that this approach should be even more effective when administered during earlier stages of the pathologic process, what we refer to as the “pre-clinical” phase, when amyloid is building up in the brain, but has not yet caused significant symptoms.

PBN: What possible adverse effects, if any, could be associated with the medication, theoretically?
OTT:
The anti-amyloid antibody has been already tested in more than 1,800 people in previous studies, and it shows a good safety profile so far. Small areas of bleeding (microhemorrhages) or brain swelling (edema), seen in some other antibody trials in the past, have not been seen for the antibody chosen for the A4 trial. Of course, any time a needle or intravenous infusion is used, there could be anxiety or physical discomfort during administration of the antibody.

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PBN: Was it possible for the study to do animal research before the human trials?
OTT:
There has been extensive animal research leading up to clinical trials in humans. One of the first major studies done in animals that really propelled the development of this approach to treating Alzheimer’s disease came from a study by Dr. Dale Schenk and colleagues in 1999. Remarkably, injection of amyloid proteins into transgenic mice harboring a human Alzheimer mutation that develop Alzheimer-like pathology led to reduced amyloid plaque pathology. This study was subsequently confirmed and extended by multiple groups who also demonstrated behavioral improvements in Alzheimer transgenic mice with active and passive amyloid immunization.

PBN: What is the best possible outcome of the study? Could this be a game-changer in the field of dementia?
OTT:
We hope to see at least a 30 percent reduction in decline on tests of memory and thinking over the three years, as well as significant changes in biologic markers of Alzheimer’s, such as presence of amyloid proteins in the brain and spinal fluid or brain shrinkage (atrophy) on MRI scans, demonstrating that we have actually made an impact on reducing the disease process. Over the longer term, we would also hope to be able to demonstrate that people receiving the antibody infusions were less likely to develop the actual symptoms and functional decline of Alzheimer dementia.
If successful, the A4 trial will certainly be a game changer, as it would provide a roadmap to a radically new treatment approach to this widespread, progressive and deadly disease. It has been estimated that a treatment breakthrough now that delays the age of onset of Alzheimer’s disease by five years would reduce the prevalence for those under age 65 from 10 percent to 7 percent in 2020 and from 16 percent to 9 percent in 2050. This is what we need now, before the advancing age of the baby boom generation threatens to overwhelm our health care resources with a tsunami of people with Alzheimer’s disease and other age-related disorders. As they say, “an ounce of prevention is worth a pound of cure.”

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