Efforts intensify to identify disease pathways, biomarkers that could lead to therapies
As adults with Down syndrome (DS) live longer lives, scientists are seeking to learn more about how Alzheimer’s starts and progresses in this specific population. Their work could deepen the understanding of Alzheimer’s in DS and advance efforts to find ways to better treat and prevent the brain disorder in all people.
Alzheimer’s disease is extraordinarily common in people with DS, occurring three to five times more often than in the general population. “People with DS are the largest genetically at-risk population for Alzheimer’s,” said Dr. Laurie Ryan, program director for Alzheimer’s disease clinical trials at NIA.
She added, “There is tremendous interest in the research community to better understand the disease process in people with Down syndrome and find better therapies for them. This effort also could help us discover new drugs and other treatments for others with or on the path to Alzheimer’s.”
Researchers funded by the National Institutes of Health (NIH), including NIA, are working on many fronts to explore the nexus of Alzheimer’s and DS. Basic research aims to better understand the two disorders’ common genetic and biological underpinnings. Observational studies are looking at young adults with DS to see if and how they develop Alzheimer’s. A few clinical trials  are testing potential treatments.
Extra chromosome means extra plaques
The connection between DS and Alzheimer’s, rooted in an extra chromosome 21, has long been known. Over the past 30 years, the average lifespan of people with DS has doubled to 60 years, and Alzheimer’s symptoms often begin when they are in their 50s and 60s. In the general population, dementia symptoms typically do not become evident until people are in their 60s or 70s.
People with DS are born with an extra copy of chromosome 21, the result of a random error in cell division. Having three copies of chromosome 21, instead of the normal two, leads to a host of cognitive and physical symptoms, including a mild to moderate intellectual disability and distinctive facial features. As they age, people with DS are at higher risk for health conditions ranging from cataracts and hearing loss to heart defects and hypothyroidism.
The extra copy of chromosome 21 in DS also means a higher risk of Alzheimer’s disease. That chromosome contains the APP gene, which produces amyloid precursor protein. In early-onset Alzheimer's, a rare, inherited form of the disorder, mutations in the APP gene cause amyloid precursor protein to be produced. This leads to the formation of harmful beta-amyloid plaques in the brain characteristic of Alzheimer’s.
For most of their lives—starting in infancy, some studies show—people with DS, given their extra copy of the APP gene, churn out lots of amyloid precursor protein. By middle age, the accumulated plaques, along with deposits of another protein called tau, wreak biological havoc in the brain, resulting in Alzheimer’s in most, but not all, adults with DS. About one-third of people with DS in their 50s have Alzheimer’s dementia; in their 60s, at least half do.
Impetus for DS research and services
Scientists have studied DS since British doctor J. Langdon Down first described the disorder in 1866. Recently, the connection between DS and dementia has garnered increased attention from the Alzheimer’s community.
Under the National Plan to Address Alzheimer’s Disease , the Federal Task Force on Specific Populations was charged with suggesting ways to improve care for specific populations that are “unequally burdened” by Alzheimer’s disease, including people with DS, people with younger-onset dementia, and racial and ethnic minorities. The task force’s report , issued in June, recommends improvements in care and services, such as increasing awareness of advance care planning and relevant clinical trials.
The Plan also directs research attention to this issue. In April, the NIA co-sponsored a conference to help set a research agenda aimed at speeding the development of possible therapies to treat Alzheimer’s in DS. Representatives from academia, industry, federal agencies, and private foundations explored topics such as the Alzheimer’s disease pathway, animal models, biomarkers, and cognitive assessments. Other co-sponsors included the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)  and the National Institute of Neurological Disorders and Stroke , both part of NIH; the Down Syndrome Research and Treatment Foundation ; and Research Down Syndrome .
Molecules, MRIs, and more
Current NIA-funded research about Alzheimer’s in DS focuses primarily on basic studies or epidemiological or observational studies that help define risk factors or measure the course of the disease. Some studies seek to uncover the specific molecular and genetic processes at work. Others follow study volunteers with DS as they age to look for correlations between brain changes and changes in cognition.
A few clinical trials have been conducted and others are in the works, but “we have to better understand the course of the disease before finding treatments to test,” said Dr. Frederick Schmitt of the Sanders-Brown Center on Aging, an NIA grantee at the University of Kentucky in Lexington. Dr. Schmitt and colleague Dr. Elizabeth Head are conducting a 5-year study of adults with DS , funded by NICHD, to identify how dementia develops in adults with DS over age 35 by looking at cognitive-test results, certain proteins in blood, and connections between brain regions measured by a type of magnetic resonance imaging (MRI) called diffusion tensor imaging.
What scientists know so far is that, aside from earlier onset, Alzheimer’s in people with DS looks a lot like Alzheimer’s in others. Risk increases with age. Cognitive impairment starts with memory loss and other thinking problems, though people with DS initially tend to show behavior changes and problems with walking. The disease process is generally the same, with brain changes believed to precede signs of dementia by 10 to 15 years or so.
Several clinical studies are observing participants with DS as they get older. “Our goal is to develop biomarkers to see if we can tell who’s at greatest risk for Alzheimer’s in this population,” said Dr. Benjamin Handen, a clinical psychologist at the University of Pittsburgh, who leads an NIA-funded study in this area. “Anything we learn can help in the general population.”
Handen’s research, Natural History of Amyloid Deposition in Adults with Down Syndrome , follows volunteers age 30 and older who have DS but no dementia at the start of the study, a group at very high risk for Alzheimer’s. Investigators are documenting changes in brain amyloid, brain volume, and performance on neuropsychological tests over time. More than 60 of the 84 participants sought have enrolled in the study at the University of Pittsburgh and the University of Wisconsin-Madison.
The results of two types of brain scans—MRI and positron emission tomography with imaging agent Pittsburgh Compound B (PiB PET)—taken every 30 months are compared with those of people with Alzheimer’s but no DS and older adult controls without Alzheimer’s. “Our findings to date suggest that the pattern of amyloid deposition in people with DS is similar to that of other people with early-onset Alzheimer’s,” Handen said.
Early results also reveal a dramatic escalation in amyloid load with advancing age. According to Handen, between ages 30 and 35, none of the study participants have amyloid in the brain detectable by a PiB PET scan. But the percentage rises from 33 percent in participants age 36 to 40, to 72 percent in those age 41 to 45, to almost 80 percent in those age 46 to 50.
“The process in DS is not necessarily faster than in the general population, it just starts earlier,” Handen noted.
Alzheimer’s not inevitable in DS
One mystery to be resolved is why a person with DS may develop Alzheimer’s pathology but not show symptoms of dementia. This also occurs in the general population, as autopsy studies have shown that some people remained cognitively normal despite having Alzheimer’s plaques and tangles in the brain.
“Clearly, there are some protective factors,” Dr. Handen said, but it is not yet known what they are. Theories include “cognitive reserve,” the ability of education and cognitive training to delay dementia. Another possibility is a biological ability to resist or cope with the overproduction of beta-amyloid plaques.
As Handen and other scientists continue to investigate Alzheimer’s in DS, NIH’s NICHD plans to launch the Down Syndrome Consortium Registry  this fall. People with DS, their family members, and others will be invited to join the registry, called DS ConnectTM. Users will be able to enter highly secure profiles to access information about DS and, with their permission, be contacted about opportunities to participate in research. For more information, see NIH establishes Down syndrome patient registry .