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Researchers look to disease-modifying therapy to ward off, possibly prevent Alzheimer’s disease

Monday, December 19, 2011

Just as statins help lower high cholesterol levels to reduce the risk of heart attacks, researchers are seeking a comparable approach for people with large amounts of beta amyloid, an abnormal protein in the brain commonly found in Alzheimer’s disease patients. Medicines would clear those proteins before any signs of memory loss or other early symptoms of Alzheimer’s appear. 

Could amyloid-based drugs given at much earlier stages of Alzheimer’s—even before any clinical symptoms begin—reduce the risk and possibly prevent the emergence of cognitive impairment and dementia?  

That is the central question of a provocative commentary in the Nov. 30 issue of Science Translational Medicine, written by a trio of researchers who cite how Alzheimer’s, which affects more than one out of every 10 individuals over the age of 65, is the only leading cause of death for which no disease modifying therapy exists.

Currently, most proposed Alzheimer’s drugs are tested in patients in the later stages of the disease, because no reliable medical test, brain imaging or other method currently exists to accurately detect the disease before initial symptoms appear. Recent clinical trial failures at the dementia stage have raised multiple questions about the current development of disease-modifying therapies, prompting a strategy to begin developing and testing drugs aimed at the initial stages of the disease rather than at the end stage of the illness.  

Mounting evidence, the authors note, from natural history studies supports amyloid beta accumulation in the brain as an early biomarker and a critical event in the early progression of Alzheimer’s. Already, some studies have shown that a person’s brain may be damaged at least a decade prior to the first signs of Alzeimer’s symptoms. More than 50% of certain brain cells are already lost by the time a patient shows even the mildest cognitive impairment.  

However, it remains unclear whether the buildup of amyloid beta protein (which accumulates in the areas of the brain responsible for learning and creating, retaining and extracting memories) is an early symptom or a cause of the disease. Several small monoclonal antibody studies that reduced the amyloid plaque burden have not shown any clear benefit in the limited number of patients treated at stages of mild to moderate dementia.  

Titled “Testing the Right Target and Right Drug at the Right Stage,” the authors suggest specific amyloid-based therapies be directed at much earlier stages of Alzheimer’s—perhaps even before the emergence of clinical symptoms. “Furthermore, we argue that the field has sufficient tools to being secondary prevention trials—those conducted after the disease process has begun in hopes of preventing the emergence of symptoms—in asymptomatic individuals who are at risk for the progression of cognitive impairment and AD dementia.” 

Still, one-third of the nation’s aging baby boomers show no signs of Alzheimer’s despite an amyloid burden, prompting the researchers to ask, “How do older individuals spend years with a ‘head full of amyloid’ and remain apparently healthy? Is amyloid ‘necessary but not sufficient’ to result in cognitive impairment?”  

Clinical trials to test whether specific drugs can head off the disease at various stages of Alzheimer’s, and thinking about the disease in terms of primary, secondary and tertiary prevention, rather than lumping together all disease modifying treatments, is a first step.  

The article’s lead author, Reisa Sperling, M.D., an Alzheimer’s specialist at Brigham and Women’s Hospital in Boston, said she hopes to launch a three-year study of an amyloid clearing medication in 1,000 patients age 70 or older who have no Alzheimer’s symptoms but have amyloid plaque in their brains. The clinical trial also would be a milestone as the first known anti-amyloid drug given to people without Alzheimer’s symptoms. 

Dr. Sperling’s plan, which requires major government and industry funding, is among a trio of academic plans to pursue comparable research in populations not diagnosed with dementia, with a goal of launching studies next year, according to Maria Carrillo, M.D., senior director of medical and scientific relations for the Alzheimer’s Association.  

“Although nothing is programmed or funded yet, we are having discussions with federal regulators, the National Institutes of Health and various experts, and I think in 2012 we may see the first clinical trials,” said Carrillo, adding that both the FDA and the EMA are involved in the discussions of pre-dementia clinical studies.  

She also is optimistic that by next June the FDA could approve a brain imaging product for early amyloid plaque detection that possibly could rule out Alzheimer’s in those with no signs of the amyloid protein in their brain scans. 

“The analogy with statins, where you are treating populations with no symptoms early on, is a good one,” said Carrillo, “because we can change the course of Alzheimer’s disease to where it can be delayed, detected early, understanding changes without cognitive impairment—even avoided altogether.” 

Ronald Rosenberg

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