DuPont Challenge Science Essay Competition

Preventing Down Syndrome to Alzheimer’s Disease

by Yukai Hong

Lord Byng Secondary School
Vancouver, British Columbia
Sponsoring Teacher: Ted Fung

Second place, senior division, 2011

Studies show that 10–25% of Down syndrome patients develop Alzheimers disease by the age of 50; 20-50% by age 60, and almost all patients over 70 will have this disease (Alvarez N). Why are individuals with Down syndrome more susceptible to the development of Alzheimers disease? First, we must understand the cause and effects of both Down syndrome and Alzheimers disease.

People with Down syndrome, or Trisomy 21, are handicapped from birth due to the presence of an extra copy of chromosome 21. A recent report in the United States estimates that 1 in 800 newborns will have Down syndrome (Emma Y). These patients suffer varying degrees of mental retardation, physical growth defects, and other health issues pertaining to the heart, thyroid, eyes, and reproductive organs. These individuals also have a decreased average life expectancy of only ~50 years (Emma Y) substantially due to the early onset of Alzheimers disease (Ma H).

Alzheimers disease is a terminal form of memory loss, termed dementia. In the early stages, patients have mild difficulties recalling recent events or acquiring new knowledge. However, by the late stages, more severe symptoms such as language deterioration, long term memory loss and confusion become increasingly prevalent. Gradually, physical motor skills are lost and mental capacity is diminished, resulting in complete mental deterioration. In 2006, Alzheimers disease was reported as the seventh leading cause of death with a 2.4% mortality rate in the United States (Statistics Top 10).

Ethan was one of the few children to be born with Down syndrome. Growing up, he was teased for his sluggishness and appearance. As an adult, he would pursue refuge in his studies and weekly Special Olympics practices. Ethan helped spark my interest for Down syndrome when I began coaching with the Special Olympics three years ago. Many of the athletes I train, including Ethan, have this genetic disorder, but even so, their degrees of dedication and persistence surpassed those of normal people. Witnessing the empowering resolve of these courageous people fueled my desire to exercise the boundaries of this disease. My curiosity for the study of Down syndrome has been further stimulated over the last year through my participation in the High School Science Week program at a research center in St. Pauls Hospital. From there, I was selected to participate in the Sanofi-Aventis BioTalent competition, where I am currently under the guidance of Dr. Song at the University of British Columbia, analyzing several contributing factors to Alzheimers disease.

Scientists speculate that genes within the additional chromosome 21 may contribute to the premature development of dementia. Several candidate genes have been identified, including the amyloid precursor protein (APP) gene and the Down syndrome critical region 1 (DSCR1) gene (Ermak G/ Margallo-Lana M). Both genes are malignant when highly expressed in the brains of patients with Down syndrome and Alzheimers disease. Using genetically modified animal models, researchers have found that animals with an overexpression of these genes exhibit severe learning and memory defects, similar to those observed in Alzheimers disease patients (Chang KT/Ma H). Scientists believe that the protein products of these genes can induce abnormal protein accumulation in the nerve cells, subsequently leading to the formation of amyloid plaques and neurofibrillary tangles, characteristic to Alzheimers disease.

Despite these astonishing findings, there are no drugs to prevent or cure Alzheimers disease. Given the importance of the APP gene in the occurrence of Alzheimers disease, scientists have invested great efforts in the creation of drugs that target the APP. APP is a membrane protein expressed in many tissues. When APP is abnormally processed by enzymes (secretases), the products form beta-amyloid plaques, a hallmark of Alzheimers disease. Scientists aim to develop drugs that inhibit secratases to limit beta-amyloid production (Hills ID). This will stop the accumulation of plaques in the brain, thus preventing the disease. By blocking these enzymes in genetically modified mice, a 40% drop in beta-amyloid was observed in a period of four days. However, this may not be a practical treatment as the blockage of secretase will also inhibit its ability to assist with many other brain functions (Powell C). Extensive research is underway in many research laboratories worldwide, aiming at specificity of inhibitors to block the progression of Alzheimers disease. Although a safe, effective, and affordable drug may not be available anytime soon, it is assuring to know that Alzheimer's disease, the 7th leading cause of death in the United States can be prevented. The betterment of this drug will not only increase the life expectancy of those with Down syndrome, but will also decrease the risk for the 14% of the population that will develop Alzheimer's disease by the age of 65 (Anderson HS).

Now, Ethan has managed to achieve a rich life, owning his own apartment, having many friends, and competing in the Special Olympics. He will never cease to amaze me with his demonstration of pure athleticism and sportsmanship. Although his Down syndrome symptoms have been suppressed by treatments, he is still prone to the development of Alzheimers disease. With the combined efforts of many research labs, we can develop an effective remedy that can pave Ethan's way to a bright future.

Sources

• Alvarez R. emedicine.medscape.com/article/1136117-overview
• Emma Y. www.newscientist.com/article/dn2073
• Ma H, Xiong H, Liu T, Zhang L, Godzik A, and Zhang Z. 2004. Aggregate formation and synaptic abnormality induced by DSCR1. J Neurochem 88:1485–96
• Statistics Top 10 www.statisticstop10.com/Causes_of_Death_in_US.html
• Ermak G, Morgan TE, and Davies KJ. 2001. Chronic overexpression of the calcineurin inhibitory gene DSCR1 (Adapt78) is associated with Alzheimer's disease. J Biol Chem 276: 38787–94
• Margallo-Lana M, Morris CM, Gibson AM, Tan AL, Kay DW, Tyrer SP, Moore BP, and Ballard CG. 2004. Influence of the amyloid precursor protein locus on dementia in Down syndrome. Neurology 62: 1996–8
• Chang KT, Shi YJ, and Min KT. 2003. The Drosophila homolog of Down's syndrome critical region 1 gene regulates learning: implications for mental retardation. Proc Natl Acad Sci U S A 100:15794-9
• Hills ID and Vacca JP. 2007. Progress toward a practical BACE-1 inhibitor. Curr Opin Drug Discov Devel. 10: 383–91
• Powell C. www.utsouthwestern.edu/utsw/cda/dept353744/files/591806.html
• Anderson HS. emedicine.medscape.com/article/1134817-overview