In a new lead on Alzheimer's research, Johnson & Johnson is bankrolling a three-year pilot study of people with Down syndrome to identify the early changes that herald dementia, which afflicts up to 75 per cent of adults with the condition.
The aim is to generate support for a much bigger, public-private partnership funded by drug makers, advocates and government agencies that will study at least 1,000 people with Down syndrome, tracking them from an early age and eventually testing treatments to keep dementia from developing.
"The study we're proposing would provide insight into treating Alzheimer's, but it might help individuals with Down syndrome as well," said Dr. Husseini Manji, Johnson & Johnson's head of neuroscience drug development.
Experts in Down syndrome and Alzheimer's who gathered in Chicago for a workshop on the idea at the U.S. Alzheimer's Association offices this month say it may offer the best scientific model yet for testing drugs to prevent the degenerative brain disease.
The industry has been repeatedly stung by the failure of experimental Alzheimer's treatments, including recent trials of the Johnson & Johnson and Pfizer Inc. therapy bapineuzumab. As a result, companies and researchers are looking for ways to test Alzheimer's drugs earlier, before people's brains become too damaged to benefit.
Studies are already planned to enroll people who carry genetic mutations that ensure they will develop Alzheimer's at an early age. One trial backed by the U.S. Department of Health and Human Services will test a drug from Roche Holding AG's Genentech unit called crenezumab in an extended family from Colombia who carry a mutation that causes them to develop Alzheimer's in their 30s.
Only a few hundred families in the world carry these genes, and there is some worry that drugs tested in people with genetic mutations that cause early-onset Alzheimer's may work differently in people who develop the more common late-onset Alzheimer's, which develops after the age of 65.
The dementia that develops in people with Down syndrome may bear a stronger resemblance to the disease in the broader population because it differs from other forms of early-onset Alzheimer's, researchers say.
People with Down syndrome inherit a third copy of chromosome 21, giving them an extra helping of a gene that makes amyloid precursor protein, or APP, which is linked with the development of plaques in the brains of Alzheimer's patients.
Most early-onset Alzheimer's is caused by mutations in the APP gene or in one of two genes known as presenilin 1 or presenilin 2. People with Down syndrome appear to develop dementia because of their extra copy of an otherwise normal APP gene.
"There is a possibility that the Down syndrome population mimics [late-onset] Alzheimer's disease a little more closely," said Manji, co-author of a commentary this month in Nature Reviews Drug Discovery that laid out plans for the study.
Dementia starts much earlier in people with Down syndrome, who develop brain plaques and tangles by the age of 30 and signs of dementia by the age of 40.
The number of potential Down syndrome patients exceeds those with the genetic mutation.
"These diseases almost certainly have common features," said Dr. William Mobley of the Down Syndrome Center for Research and Treatment at the University of California, San Diego.
While all of the similarities are not yet clear, studies in mice with Down syndrome show that just eliminating just the extra copy of the gene for APP can keep brain cells from dying, he said.
Mobley's centre will run the 12-patient pilot study, which aims to lay the foundation for the larger project, dubbed the Down Syndrome Biomarker Initiative.
The larger trial would be patterned after two successful studies: the Alzheimer's Disease Neuroimaging Initiative, a public-private partnership that helped identify biomarkers linked with Alzheimer's, and a breast cancer trial known as I-SPY that pioneered adaptive trial design, in which researchers use biomarkers to match the right drug to the right patient.
What is not yet known is how many parents of people with Down syndrome would be willing to sign up their adult children for such trials. Michelle Whitten of the Global Down Syndrome Foundation thinks many will be.
Whitten, the mother of a nine-year-old with Down syndrome, says the lifespan of people with the condition has increased from 28 years in the 1980s to 60 years today because of better treatment. That means many parents who fought to give their children a good education and a worthwhile job now frequently face their decline into dementia.
"We just want it solved," Whitten said.
Dr. Michael Krems, who heads the neurology franchise at Johnson & Johnson, said the challenge is to develop drugs that offer lots of potential benefit with little risk to patients.