The first Alzheimer's-related changes begin to develop some 25 years before memory and thinking problems appear, according to a new study that may offer a valuable guide for companies looking to test new treatments in people at an earlier stage.
The study, published on Wednesday in the New England Journal of Medicine, offers a timeline of changes in spinal fluid, brain size, the appearance of brain plaques and other factors that precede the onset of Alzheimer's in people who are genetically predestined to develop the brain-wasting disease.
"It's really the first report that we have in living people of these changes," said Dr. Randall Bateman of Washington University School of Medicine in St. Louis, Missouri who helped lead the study.
Current drugs for Alzheimer's only treat symptoms and none have yet been able to keep the fatal disease from progressing. Some researchers think that may be because the disease has been studied too late in its progression.
So scientists have been searching for ways to test treatments at an earlier stage, when many researchers think new therapies will have the best shot at doing some good.
Conducting such trials in people with the common form of Alzheimer's disease would need to be huge and last for decades.
Instead, the study by the team at Washington University focuses on families enrolled in the Dominantly Inherited Alzheimer's Network, a consortium that enrolls people who are genetically predisposed to develop the disease at an early age.
"On average, patients with this form get Alzheimer's Disease by 45," Bateman said in a telephone interview.
People in these families have a 50 percent chance of inheriting one of three genes that cause early Alzheimer's and most develop symptoms around the same time as their affected parent.
Bateman followed the progress of 129 individuals and used family histories to estimate when study subjects should begin to develop Alzheimer's symptoms. They developed a timeline of changes in the body leading up to the memory loss and declines in thinking skills associated with Alzheimer's.
The first of these changes, a drop in the level of a protein known as amyloid, can be detected in spinal fluid as early as 25 years before the disease is expected to develop.
At 15 years before onset of the disease, clumps of an Alzheimer's-related protein called beta amyloid become visible on brain scans. Other scans show shrinkage of brain structures, and levels of a toxic protein called tau start to rise in spinal fluid.
At 10 years before onset, the brain becomes less adept at using glucose and some slippage in certain kinds of memory skills can be detected.
Bateman said it is not clear whether the same timeline would apply to patients who have more common late-onset Alzheimer's disease, which usually develops after age 65. But he said the biomarkers are very similar to changes already used by doctors to characterize and track the disease.
"What we don't know is if the time, the order of magnitude and the size of these changes is similar or not," Bateman said. "It may be many years before we have this information."
Researchers plan to use information from the study to test drugs on these patients before symptoms develop.
Crenezumab, an experimental Alzheimer drug made by Roche's Genentech unit has already been selected for a similar kind of test in a large family of people in Colombia who develop early onset Alzheimer's disease.
While Bateman would not say which drugs will be tested in the study, he said they will likely test three compounds "that we think represent some of the best and most advanced compounds in development."
Results of two of the most advanced drugs being studied are expected this fall. They include late-stage studies of bapineuzumab being developed by Pfizer and Johnson & Johnson, and solanezumab, being developed by Eli Lilly .
Another drug in late-stage trials is intravenous immunoglobulin, an immune system treatment being studied by Baxter International Inc.
As many as five million Americans have Alzheimer's and the clock is ticking to find a cure.
Experts predict that without an effective treatment, the number of Americans with Alzheimer's will double by 2050 to more than 10 million, and related healthcare costs could soar to over $1 trillion a year.
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