Down’s syndrome (DS) and Alzheimer’s disease (AD) are inextricably linked. People with Down’s carry a third copy of the amyloid precursor protein (APP) gene on their triplicated chromosome 21, and are almost certain to develop amyloid pathology and dementia. Research on either condition could lead to better understanding and treatments for both. In recognition of that potential, two initiatives are underway to explore dementia in DS. A pilot will soon kick off the Down Syndrome Biomarker Initiative (DSBI), a natural history observation study that could provide diagnostic or prognostic markers for future clinical trials. In addition, three foundations have together launched a new research grants program dedicated to the study of AD in DS.

“Finally there’s real movement in this research area,” said William Mobley, University of California, San Diego. “People are understanding the importance of making early diagnoses, and that this population provides a large group of people in whom pathogenesis can likely be studied decades before there are symptoms.”

Scientists from Janssen Pharmaceuticals in New Jersey, in collaboration with the Alzheimer’s Disease Cooperative Study, and Down Syndrome Center for Research and Treatment at the University of California, San Diego, are gearing up for a pilot DSBI (see Ness et al., 2012). Researchers will track neuropsychological test performance, brain amyloid by PET amyloid imaging, volumetric magnetic resonance imaging (MRI), and blood biomarkers in 12 volunteers over three years to see how each factor relates to the others and changes over time. They will also examine retinal amyloid by imaging spice-derivative curcumin, which when taken orally can travel to the retina where it binds amyloid and fluoresces. Researchers hope to confirm that this technique could pick up early AD, figure out how retinal amyloid changes with disease progression, and determine whether it might serve as a marker of treatment success (see Koronyo et al., 2012). Scientists hope to organize a public-private partnership to fund the main DSBI project, which would enroll 1,000 people and run for five years.

The DSBI echoes the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN) with an added twist—the DSBI has been designed from the get-go to provide a basis for future clinical trials of AD therapies. As is the case in DIAN, after five years of data collection to establish baseline trajectory in the observational DSBI study, volunteer participants may enter into clinical trials testing interventions that might slow or halt disease progression. “It will dramatically change the way we learn,” said Michael Krams from Johnson and Johnson. “We will no longer know very little about patients when they enter a clinical trial; rather, we will know something about the trajectory before and after treatment intervention.” Since DS is more prevalent than familial early onset AD but individuals are almost as likely to develop dementia, and since Aβ pathology progresses with a similar trajectory to that in AD patients, the DS population could bolster the number of people available for clinical trials.

If a public-private infrastructure can be built, it may even be possible to compare similar, competing compounds or combinations in one umbrella-like clinical trial platform. This is already being done in the I-SPY2 Phase 2 trial that compares different companies’ drugs for breast cancer (see ARF related news story). “Then we can figure out which of the many treatments that we have in play will solve the problem best,” Krams told Alzforum.

A separate funding initiative also aims to stimulate research in DS and AD. The Alzheimer’s Association, the Linda Crnic Institute for Down Syndrome at the University of Colorado in Aurora, and the Global Down Syndrome Foundation in Denver, together committed $1.2 million over three years to fund new research into dementia in DS. “[This funding] is great news,” said Ahmad Salehi, Stanford Medical School, Palo Alto, California, who made the transition from AD research to DS partly because he realized the potential for modeling AD. “We need far more [funds] to study DS thoroughly, but this is a welcome start.” The stimulus comes at a time when researchers and advocates are strongly urging additional spending to tackle the AD epidemic. Three-year grants will be awarded to established researchers or new investigators in the amounts of $300,000 or $150,000, respectively. By drawing attention to the topic with this initial funding, the Association hopes to attract interest from the public and private sectors to fund more projects down the road, said Dean Hartley of the Association’s Chicago headquarters (see Request for Applications).

A funding initiative that looks at pathogenic mechanisms, blood and brain biomarkers, and diagnostic methods will help generate a broad overview of dementia in DS and lead to better information sharing, said Nicole Schupf, Columbia University, New York. Schupf is interested in looking at how other genes on the triplicated chromosome 21 may contribute to AD, and why there is such variation in pathology and age of dementia onset in people with DS.

Families with DS welcomed the funding news. “We think it’s going to be very important,” said Jack Dorwart of Denver, Colorado, whose 34-year-old son has Down’s. “This will make it possible for researchers to not just dabble around the edges of this research, but really do something significant,” said Dorwart. He has seen the beginnings of dementia in family friends with Down’s and worries about his son. “The concern is that you work so hard to get [them] to do so well,” said his wife, Penni Dorwart. “It’s amazing how quick the downturn can be if Alzheimer’s enters the picture.”

More information about due dates, award requirements, and a list of suggested research topics can be found here.—Gwyneth Dickey Zakaib.


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News Citations

  1. Can Adaptive Trials Ride to the Rescue?

Paper Citations

  1. . Down's syndrome and Alzheimer's disease: towards secondary prevention. Nat Rev Drug Discov. 2012 Sep;11(9):655-6. PubMed.
  2. . Alzheimer's disease in the retina: imaging retinal aβ plaques for early diagnosis and therapy assessment. Neurodegener Dis. 2012;10(1-4):285-93. PubMed.

External Citations

  1. I-SPY2
  2. Request for Applications

Further Reading


  1. . Down's syndrome and Alzheimer's disease: towards secondary prevention. Nat Rev Drug Discov. 2012 Sep;11(9):655-6. PubMed.
  2. . Imaging brain amyloid in nondemented young adults with Down syndrome using Pittsburgh compound B. Alzheimers Dement. 2012 Nov;8(6):496-501. PubMed.
  3. . Modulating cognitive deficits and tau accumulation in a mouse model of aging Down syndrome through neonatal implantation of neural progenitor cells. Exp Gerontol. 2012 Sep;47(9):723-33. PubMed.
  4. . Trisomy for Synaptojanin1 in Down syndrome is functionally linked to the enlargement of early endosomes. Hum Mol Genet. 2012 Jul 15;21(14):3156-72. PubMed.