Research to unravel for the first time the complex genetic mechanisms shared by Alzheimer’s disease and Down syndrome is gaining momentum in studies by Johnson & Johnson
and patient advocacy groups.
By age 40, almost everyone with Down syndrome has beta amyloid deposits in their brains reflective of the protein clumps seen in Alzheimer’s in the general population, autopsy and imaging studies show. By age 50, half have dementia.
While the high incidence in Down patients has been noted for decades, scientists are only now seeking to use the quicker progression to gauge how Alzheimer’s grows in the general population. At a time when drug companies have been frustrated in their efforts to slow the disease, the link to Down syndrome may hold the promise of a new path forward toward finding an effective treatment.
“In a way, Down syndrome is a model disease for Alzheimer’s,” said Mike Krams, vice-president of quantitative sciences at J&J’s Janssen Pharmaceuticals unit, which will meet Nov. 15 to discuss a three-year pilot study.
Not everyone with Down syndrome shows signs of dementia as they age, even as the amyloid accumulates. Finding out what prevents Alzheimer’s in these patients may provide clues for the general population, Krams said by telephone.
The New Brunswick, New Jersey-based company is developing a drug meant to stop or slow beta amyloid formation by preventing a parent protein from being cut into smaller parts. Because Down syndrome patients have extra amounts of this precursor protein, they may benefit from that drug, Krams said.
At the same time, five researchers in the U.S. and Israel last month were awarded a combined $1.2 million to investigate aspects of the link between the diseases in an effort bankrolled by the Global Down Syndrome Foundation in Denver and the Chicago-based Alzheimer’s Association.
Studies into Down syndrome have long presented challenges and are often blocked by family members or legal guardians. Now, using improved genetic data, new scanning technology and better cognitive testing, researchers in both diseases are able to gather data in a bid to track Alzheimer’s progress in living patients, rather than having to wait to perform autopsies.
“Most people who study Alzheimer’s disease don’t really see individuals with Down syndrome frequently,” said Ira Lott, head of the University of California at Irvine’s Down syndrome program. “It’s been a matter of cross-communication.”
The grant to the five researchers was awarded Oct. 29, and is designed to support work that is investigating the interplay of certain genes that may lead to overproduction of beta amyloid; whether certain biomarkers can be used to track disease progression in Down Syndrome patients; and if it’s possible to create a DNA vaccine.
Researchers will be starting their work as life expectancy of those with Down syndrome has doubled to age 60 over the last 30 years, according to the National Institutes of Health.
About 6,000 babies are born yearly in the U.S. with the syndrome
, which occurs as the result of an extra copy of chromosome 21 passed to them in the womb. No one knows why this happens and, in the past, heart defects and thyroid trouble linked to the condition, as well as neglect in institutions, meant that most people with the condition died before their 30s.
As patients lived longer, scientists began to notice the link to Alzheimer’s, and research in the last 20 years, primarily based on autopsy results, determined that the accumulation of beta amyloid begins much earlier in this group than in the general population.
J&J said in September it would finance a University of California at San Diego study into the link between the disorders. Krams said he will meet with other scientists involved in the research on Nov. 15 to plan the next steps and seek participation from all leading U.S. Down syndrome centers.
“In the best of all worlds, we could establish a proof of concept for treatment in Down subjects,” Krams said.
The genetic error that causes Down syndrome occurs when either the sperm or egg is formed, giving the fetus an extra chromosome 21, bringing the total in every cell of the body to 47 rather than 46. This defect is linked to slow physical and intellectual development, heart issues, stomach and hearing difficulties, and a higher likelihood of childhood leukemia.
The duplicated chromosome may also cause quicker growth of beta amyloid in the brain because it carries the precursor protein for amyloid, said Ann-Charlotte Granholm at the Medical University of South Carolina, in Charleston, one of the five scientists who received the patient advocate grant.
Using mice given the extra chromosome, Granholm is working to determine if an overabundance of beta amyloid is a single cause for the progression of dementia in Down syndrome patients or if other factors are in play as well.
Those other factors may include insufficient growth factors in the brains of those with Down syndrome, or oxidative stress and inflammation, she said in a telephone interview.
“The growth factors are crucial for memory processing and learning,” Granholm said. “The task before us now is to investigate how these processes interact with amyloid.”
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