- Research & Clinical Trials
- Cutting-Edge Alzheimer’s Research
- Successful Aging Program
- The 90+ Study
- Down Syndrome Program
- Clinical Trials
- Training Grant Preceptors
Learning about healthy aging and Alzheimer’s disease from people with Down syndrome
Ira T. Lott, M.D.
Down syndrome is the most common cause of genetically-determined intellectual disability in the United States, affecting approximately 1 in 700 live births. An estimated 350,000 Americans have Down syndrome. Also called trisomy 21, Down syndrome results from a tripling of all or part of the 21st chromosome. The association between Down syndrome and Alzheimer’s disease was established in 1948. Since then, we’ve learned that by age 40, all individuals with trisomy 21 have the characteristic amyloid plaques and neurofibrillary tangles of Alzheimer’s disease.
One cause of the association between Down syndrome and Alzheimer’s disease is overexpression of the amyloid-precursor-protein gene on chromosome 21, which results in brain amyloid accumulation from an early age. Indeed, primitive brain deposits of amyloid have been seen as early as four months of age in infants with Down syndrome. As a result, the processes of development and aging in Down syndrome provide a unique window on the mechanisms that lead to Alzheimer’s disease in a young adult population. UCI MIND is one of the few research centers nationwide that has had a longstanding and robust program in Down syndrome research.
Importantly, despite the fact that plaques and tangles are essentially universal by age 40 years, not every individual with Down syndrome develops dementia. While the prevalence of dementia increases with age, we follow many individuals in their 60s and beyond who have not experienced cognitive decline. The biomarkers that may signal cognitive decline are the subject of a current major research project funded by the National Institutes of Health (NIH) that involves many UCI MIND researchers.
We do know that amyloid is first deposited in the frontal lobe and entorhinal cortex of young adults with Down syndrome. These brain areas govern emotional reaction, executive functioning and memory processes. Although the brain cells appear normal in patients with these early plaques, the neurons have a certain chemical profile which, in later life, results in apoptosis or “cell death.” While this finding is of grave concern, it also provides a basis for hope, if a therapy for dementia that is safe, tolerable and effective is found for older adults with Down syndrome, then stepping the intervention back to earlier age epochs may improve cognition in children and young adults with the disorder. This type of therapeutic window is largely unique to Down syndrome and unites the efforts of both pediatric and adult researchers.
Given the possibility of intervening early in life, individuals with Down syndrome would seem to be prime candidates for therapeutic trials. Unfortunately, until recently the opposite was true. It was said that the developmental disability made it impossible to diagnose dementia in Down syndrome or carry out successful clinical trials. Nonsense. Tests to accurately diagnose and follow dementia in Down syndrome have been developed at UCI and elsewhere. We published the first clinical trial for dementia in Down syndrome in 2002 and since that time many clinical trials have been forthcoming by our group and others. Under support of a previous NIH grant we successfully conducted a two-year randomized double-blind placebo-controlled trial of a therapeutic agent in Down syndrome with the same parameters as a major clinical trial for dementia in the general population. In fact, our researchers have found that people with Down syndrome are a joy to work with. The social skills of individuals with Down syndrome often exceed their intellectual strengths and their willingness to help enables full participation in trials that may benefit the aging process.
Clinical intervention trials, however, have reduced chance of being effective once dementia has begun in individuals with Down syndrome. We face the same challenge as Alzheimer’s disease researchers: to predict cognitive decline in order to begin intervention early. We have recently shown that seizures hasten cognitive decline in demented individuals with Down syndrome. Advanced EEG techniques may afford an opportunity for predicting dementia in Down syndrome. The “amyloid burden” in the brain can now be assessed with sophisticated functional brain imaging, as can levels of amyloid and other suspect compounds in the spinal fluid. Measures of oxidative stress in mitochondria may provide another means of predicting cognitive decline. In sum, ongoing research on Down syndrome at UCI MIND is focused on creating a predictive model of dementia in this population that will facilitate earlier intervention as new medications become available.
People with Down syndrome represent a health disparity for clinical trials. Many individuals live far from resources like our program at the UCI Medical Center and have typically been excluded as subjects for ongoing investigations. To begin remedying this disparity, we have been pioneering the use of telemedicine to reach individuals who live remotely from our medical facilities. Telemedicine is simply defined as the use of health care technology to render medical care when distance separates the doctor and the patient. In our program, the physician sees the patient in real time on a wide-screen TV and the patient sees the doctor in the same manner. We have carried out nearly 1,500 consultations in neuro-telemedicine and are convinced of both the reliability of and consumer satisfaction with this technology. Home monitoring of individuals with dementia is the next frontier for telemedicine and UCI is hard at work in developing technologies that will work efficiently for doctor and patient.
Notably, there are some ways in which individuals with Down syndrome display healthy aging that may be informative to geriatricians and Alzheimer’s disease researchers. There seems to be a paucity of atherosclerotic complications in adults with Down syndrome as they age. In our database of several hundred adults, we have found no major complications from heart attacks, hypertension, or stroke. This experience is mirrored in other clinics for Down syndrome across the country. Also, adults with Down syndrome have a decreased frequency of certain types of solid tumors. These characteristics of people with Down syndrome may shed light on fundamental processes related to development and aging. By helping individuals with Down syndrome, we not only ensure that they have the highest possible quality of life but also help ourselves to age successfully.
We wish to acknowledge the National Institutes of Health and the State of California for supporting our research and the Down Syndrome Association of Orange County for their generous funding of our pediatric clinic.