The Road from Down Syndrome to Alzheimer’s Disease

Given my sister’s history, I often wished she had Down syndrome. I’m sure that sounds odd, but when I was a kid, not to me. Jill was found to have Cornelia de Lange Syndrome (CdLS), a genetic disorder that bestows odd facial features and a small head, small stature, profuse body hair, heart problems, difficulty with eating, and often, interpersonal challenges and delayed development. Jill’s IQ was said to be 47, and she became cruelly violent within our family and with strangers from early on. Her body failed her and she died at 45, with a body that seemed more like 85, doctors said. Children with Down syndrome were in her class at school, and they seemed much more companionable, gentle, sentient, and well. As a kid, I would have preferred those traits for my sis. As with most things, the big picture gets more complicated over time. A new study by researchers at Sanford-Burnham uncovers the process that leads to changes in the brains of people with Down syndrome—changes that are just like those that cause dementia in Alzheimer’s patients. This knowledge may be helpful in the evolution of treatments that could hinder damage in neuronal connectivity and brain function in people with Down syndrome and other brain-associated conditions, Alzheimer’s included. A characteristic of those with Down syndrome (the most frequent genetic disorder) is an extra copy of chromosome 21. Most people with Down syndrome have a mild to moderate intellectual disability, and, science tells us, an increased risk of developing Alzheimer’s disease. By the time nearly all people with Down syndrome turn 40, they develop changes in the brain associated with Alzheimer’s disease, and about one-quarter of people with Down syndrome show signs of Alzheimer’s-type dementia by the age of 35, and three-quarters by the time they’re 65. Decades ago, these individuals may have only lived to 25, but now many live to 60 and beyond. The research team found that a protein called sorting nexin 27 (SNX27) regulates beta-amyloid generation. (Beta-amyloid, a sticky protein, is deadly to neurons.) Beta-amyloid and dead neurons combine to form plaques, a pathological characteristic of Alzheimer’s disease, and a potential culprit of dementia symptoms. Further, they discovered that by adding new copies of the SNX27 gene to the brains of Down-syndrome mice, they could restore the mices’ memory defect. In a Sanford-Burnham Science blog post, Susan Gammon, PhD, says the researchers have shown how lower levels of SNX27 in Down syndrome are the result of an extra copy of an RNA molecule encoded by chromosome 21 called miRNA-155 (a small bit of genetic material that influences the production of SNX27). She says the team can piece together the whole process—the extra copy of chromosome 21 causes elevated levels of miRNA-155 that in turn lead to reduced levels of SNX27. Reduced levels of SNX27 lead to an increase in the amount of active gamma-secretase causing an increase in the production of beta-amyloid and the plaques observed in affected individuals. The team hopes to devise a screening test to identify molecules that can lower the levels of miRNA-155 and restore the level of SNX27, and discover molecules that can enhance the interaction between SNX27 and gamma-secretase. Photo: Amyloid plaques are found in the brains of people with Down syndrome and Alzheimer's disease. (Photo credit: Sanford-Burnham)