1. Introduction
Down syndrome (DS), a genetic disorder that causes patients to have one more chromosome in the 21st chromosome pair. People who get Down syndrome disease always have problems with physical [1]. As more profound studies have been done recently, many researchers have found that Down syndrome is related to Alzheimer’s disease. Alzheimer’s disease is a typical progressive disease that worsens, and many patients with this disease may have problems with poor memory and even problems with communication [2]. Patients who have Alzheimer’s disease may only have a 3 to 7-year life expectancy [3,4].
Alzheimer’s disease is a disease that has existed for a long time, and the leading cause of this disease is the molecular mechanism of Tau protein aggregation in a particular position in the brain, such as the hippocampus, neocortex, and amygdala. However, 15% of patients have Alzheimer’s because of a genetic mutation. While patients with Down syndrome(DS) have a higher risk of getting Alzheimer’s disease(AD), this is because chromosome 21 always expresses APP, a kind of protein that leads to the occurrence of Aβ (a kind of protein that causes AD). Furthermore, one more trisomy 21 chromosome would over-express the APP [4], since the mRNA for producing protein APP is rising. Often, the risk of those DS patients increases as their age increases. Most patients above 40 years are constantly diagnosed with AD because there are a lot of neuritic plaques and neurofibrillary tangles [5.6.7] which are the disease can be found in the early year of 15 years old.
2. Methodology
The method used is a literature review, searching for papers and pieces of literature using Google Scholar. The papers read are highly related to this research question, which comes from putting keywords to Google and then checking out the publish time, the types of articles, and the latest studies. The most famous publications will be used in this paper.
This paper will mainly focus on How Alzheimer’s disease in Down syndrome is caused in the molecular level and in genetics and also will introduce the treatments for this disease by using choline in detail and mention other therapies, as well as the limitations of them at the end of this paper.
3. Therapies
3.1. Supplement of Additional Choline during Pregnancy
The experiment on the Ts65Dn mouse is carried out to prove that choline during pregnancy is an effective method for patients. Ts65Dn mouse is a kind of mouse that is used in experiments with trisomy chromosomes 16 and 17. Those mice show fundamental morphological, biochemical, and transcriptional changes similar to those seen in patients with DS and AD [8-13]. This means the Ach level is relatively low; this change can lead to neurons’ differentiation and plasticity of synapse formation [14-16]. So, if there is an additional supply of choline, it can help with the AD in DS for babies.
Choline has many impacts on mice, including emotion reactivity and metabolism [17]. The experiment of the Ts65Dn mouse can show the impact of choline. Before the start of the experiment, mice had difficulties concentrating on things [18,19]. And researchers found that mice can pay attention to a thing more accurately if their mother took choline [19]. Moreover, choline also reduces negative emotion in mice, and they were less influenced by failure. Also, when researchers test the activity of liver, blood, frontal cortex, hippocampus, cerebellum and basal forebrain [20], they found the activity of those organs. For instance, liver activity improved by 60% and promoted cognitive function [20].
As most of us know, Down syndrome is a disease that can be detected before giving birth to a baby by amniocentesis so that doctors can find out whether there is an additional chromosome in this baby. However, the fact now is that there is no effective treatment for ID (intellectual disability and Alzheimer’s disease) [17]. Fortunately, supplying additional choline during pregnancy improves the situation of Down Syndrome and Alzheimer’s Disease, as a therapy for those who do not know if the baby can get the ID [17]. In the animal models, researchers found that those mice with DS may have neuron atrophy, and there is only a little choline in their hippocampus, as mentioned before [9,21-24] Cognitive disability is related to 2 kinds of choline in humans: one is explicit memory, and another one is the working memory. As a result, adding choline can prevent the decay of the cognitive and also the loss of memory.
3.2. Other Choline Therapy for Down Syndrome and Alzheimer’s Disease
Instead of using choline during pregnancy or medicine that patients took for precaution, there is another acetylcholinesterase inhibitor for patients to use. And there is a study prove the availability and security of this kind of therapy. Patients who are selected need to take up 5mg placebo or donepezil randomly in the first 4 days and 10mg in following days [25]. Researchers take a record of patients Dementia Scale of Mentally Retarded Persons (DMRP) and Neuropsychiatric Inventory (NPI) [25]. This treatment also has a similar mechanism for curing by regulating the activities of cholinergic neurotransmitters [25]. There are three kinds of acetylcholinesterase inhibitor (AChE): donepezil (Aricept), rivastigmine (Exelon) and galantamine (Reminyl). But in this study these results indicate that donepezil has significant effects, which improves around 50% patients state of an illness [25]. However, further studies are needed to carry out since there are also some side effects for some patients such as insomnia and sleepy.
3.3. Potential Secondary Prevention for Alzheimer’s Disease in Down Syndrome
More results find that other secondary treatments can be used besides the choline. Many therapies focus on the AD disease and the later stages, but there are more expectations for the treatment for the earlier stage. It is now coming true because of advanced technology such as PET for patients with DS who have a higher risk of having Alzheimer’s disease. Now, a research which is called the Down Syndrome Biomarker Initiative (DSBI) is working on this trial, which ranges from memory, learning and executive function and tries to deal with Alzheimer’s disease in Down syndrome in the early stage [26].
4. Discussion for Therapies
There are only a limited number of treatments for Alzheimer’s disease and Down syndrome. The study of additional maternal choline supplement has already shown great success in these experiments. However, though researchers found that it is valuable and beneficial on Ts65Dn mouse, it cannot prove that it can still work in the human body, though both mice and humans have similar brain structures. The use of cholinesterase also plays a significant role in this disease. The main problem is that the sample that can be used is limited because this experiment is based on humans, so it needs others’ agreement. Another difficulty is that the patients have a higher possibility of getting complications.
5. Conclusion
Trisomy 21 might cause AD in older ages. However, the technology now can also help detect DS and AD, and the prevention of taking choline during pregnancy can be helpful for babies. Even for those who get AD in DS when growing up, another kind of cholinesterase can be used in the treatment. Though there still exist many obstacles that researchers should overcome, the treatment of AD in DS is ripening gradually now, so there will be fewer patients suffering from AD and DS now.
References
[1]. Patterson, David. “Molecular Genetic Analysis of Down Syndrome.” Human genetics 126 (2009): 195-214. Print.
[2]. Querfurth, Henry W, and Frank M LaFerla. “Alzheimer’s Disease.” New England Journal of Medicine 362.4 (2010): 329-44. Print.
[3]. Todd, Stephen, et al. “Survival in Dementia and Predictors of Mortality: A Review.” International journal of geriatric psychiatry 28.11 (2013): 1109-24. Print.
[4]. Rumble, Baden, et al. “Amyloid A4 Protein and Its Precursor in Down’s Syndrome and Alzheimer’s Disease.” New England Journal of Medicine 320.22 (1989): 1446-52. Print.
[5]. Wisniewski, KJDH, et al. “Precocious Aging and Dementia in Patients with Down’s Syndrome.” Biological Psychiatry 13.5 (1978): 619-27. Print.
[6]. Wisniewski, KE, HM Wisniewski, and GY Wen. “Occurrence of Neuropathological Changes and Dementia of Alzheimer’s Disease in Down’s Syndrome.” Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society 17.3 (1985): 278-82. Print.
[7]. Mann, David MA, and Margaret M Esiri. “The Pattern of Acquisition of Plaques and Tangles in the Brains of Patients under 50 Years of Age with Down’s Syndrome.” Journal of the neurological sciences 89.2-3 (1989): 169-79. Print.
[8]. Antonarakis, Stylianos E, et al. “Differential Gene Expression Studies to Explore the Molecular Pathophysiology of Down Syndrome.” Brain research reviews 36.2-3 (2001): 265-74. Print.
[9]. Holtzman, David M, et al. “Developmental Abnormalities and Age-Related Neurodegeneration in a Mouse Model of Down Syndrome.” Proceedings of the National Academy of Sciences 93.23 (1996): 13333-38. Print.
[10]. Reeves, Roger H, et al. “A Mouse Model for Down Syndrome Exhibits Learning and Behaviour Deficits.” Nature genetics 11.2 (1995): 177-84. Print.
[11]. Davisson, Muriel T. “Segmental Trisomy of Murine Chromosome 16: A New Model System for Studying Down Syndrome.” Prog. Clin. Biol. Res. 360 (1990): 263-80. Print.
[12]. Pinter, Joseph D, et al. “Neuroanatomy of Down’s Syndrome: A High-Resolution Mri Study.” American Journal of Psychiatry 158.10 (2001): 1659-65. Print.
[13]. Davisson, Muriel T. “Segmental Trisomy of Murine Chromosome 16: A New Model System for Studying Down Syndrome.” Prog. Clin. Biol. Res. 360 (1990): 263-80. Print.
[14]. Abreu-Villaça, Yael, Cláudio C Filgueiras, and Alex C Manhães. “Developmental Aspects of the Cholinergic System.” Behavioural brain research 221.2 (2011): 367-78. Print.
[15]. Albright, Craig D, et al. “Choline Availability Alters Embryonic Development of the Hippocampus and Septum in the Rat.” Developmental Brain Research 113.1-2 (1999): 13-20. Print.
[16]. Lauder, JM, and UB Schambra. “Morphogenetic Roles of Acetylcholine.” Environmental health perspectives 107.suppl 1 (1999): 65-69. Print.
[17]. J Strupp, Barbara, et al. “Maternal Choline Supplementation: A Potential Prenatal Treatment for Down Syndrome and Alzheimer’s Disease.” Current Alzheimer Research 13.1 (2016): 97-106. Print.
[18]. Driscoll, Lori L, et al. “Impaired Sustained Attention and Error-Induced Stereotypy in the Aged Ts65dn Mouse: A Mouse Model of Down Syndrome and Alzheimer’s Disease.” Behavioral Neuroscience 118.6 (2004): 1196. Print.
[19]. Moon, Jisook, et al. “Perinatal Choline Supplementation Improves Cognitive Functioning and Emotion Regulation in the Ts65dn Mouse Model of Down Syndrome.” Behavioral neuroscience 124.3 (2010): 346. Print.
[20]. Yan, Jian, et al. “Maternal Choline Supplementation Programs Greater Activity of the Phosphatidylethanolamine N-Methyltransferase (Pemt) Pathway in Adult Ts65dn Trisomic Mice.” The FASEB Journal 28.10 (2014): 4312. Print.
[21]. Hunter, Christopher L, Heather A Bimonte, and Ann-Charlotte E Granholm. “Behavioral Comparison of 4 and 6 Month-Old Ts65dn Mice: Age-Related Impairments in Working and Reference Memory.” Behavioural brain research 138.2 (2003): 121-31. Print.
[22]. Granholm, Ann-Charlotte E, Linda A Sanders, and Linda S Crnic. “Loss of Cholinergic Phenotype in Basal Forebrain Coincides with Cognitive Decline in a Mouse Model of Down’s Syndrome.” Experimental neurology 161.2 (2000): 647-63. Print.
[23]. Holtzman, David M, et al. “Mouse Model of Neurodegeneration: Atrophy of Basal Forebrain Cholinergic Neurons in Trisomy 16 Transplants.” Proceedings of the National Academy of Sciences 89.4 (1992): 1383-87. Print.
[24]. Cooper, Jonathan D, et al. “Failed Retrograde Transport of Ngf in a Mouse Model of Down’s Syndrome: Reversal of Cholinergic Neurodegenerative Phenotypes Following Ngf Infusion.” Proceedings of the National Academy of Sciences 98.18 (2001): 10439-44. Print.
[25]. Prasher, Vee P, et al. “A 24‐Week, Double‐Blind, Placebo‐Controlled Trial of Donepezil in Patients with Down Syndrome and Alzheimer’s Disease—Pilot Study.” International Journal of Geriatric Psychiatry 17.3 (2002): 270-78. Print.
[26]. Ness, Seth, et al. “Down’s Syndrome and Alzheimer’s Disease: Towards Secondary Prevention.” Nature Reviews Drug Discovery 11.9 (2012): 655-56. Print.
Cite this article
Peng,L. (2024). The relations between AD and DS and the therapies for curing this disease. Theoretical and Natural Science,45,75-78.
Data availability
The datasets used and/or analyzed during the current study will be available from the authors upon reasonable request.
Disclaimer/Publisher's Note
The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of EWA Publishing and/or the editor(s). EWA Publishing and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
About volume
Volume title: Proceedings of the 2nd International Conference on Modern Medicine and Global Health
© 2024 by the author(s). Licensee EWA Publishing, Oxford, UK. This article is an open access article distributed under the terms and
conditions of the Creative Commons Attribution (CC BY) license. Authors who
publish this series agree to the following terms:
1. Authors retain copyright and grant the series right of first publication with the work simultaneously licensed under a Creative Commons
Attribution License that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this
series.
2. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the series's published
version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial
publication in this series.
3. Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and
during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See
Open access policy for details).
References
[1]. Patterson, David. “Molecular Genetic Analysis of Down Syndrome.” Human genetics 126 (2009): 195-214. Print.
[2]. Querfurth, Henry W, and Frank M LaFerla. “Alzheimer’s Disease.” New England Journal of Medicine 362.4 (2010): 329-44. Print.
[3]. Todd, Stephen, et al. “Survival in Dementia and Predictors of Mortality: A Review.” International journal of geriatric psychiatry 28.11 (2013): 1109-24. Print.
[4]. Rumble, Baden, et al. “Amyloid A4 Protein and Its Precursor in Down’s Syndrome and Alzheimer’s Disease.” New England Journal of Medicine 320.22 (1989): 1446-52. Print.
[5]. Wisniewski, KJDH, et al. “Precocious Aging and Dementia in Patients with Down’s Syndrome.” Biological Psychiatry 13.5 (1978): 619-27. Print.
[6]. Wisniewski, KE, HM Wisniewski, and GY Wen. “Occurrence of Neuropathological Changes and Dementia of Alzheimer’s Disease in Down’s Syndrome.” Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society 17.3 (1985): 278-82. Print.
[7]. Mann, David MA, and Margaret M Esiri. “The Pattern of Acquisition of Plaques and Tangles in the Brains of Patients under 50 Years of Age with Down’s Syndrome.” Journal of the neurological sciences 89.2-3 (1989): 169-79. Print.
[8]. Antonarakis, Stylianos E, et al. “Differential Gene Expression Studies to Explore the Molecular Pathophysiology of Down Syndrome.” Brain research reviews 36.2-3 (2001): 265-74. Print.
[9]. Holtzman, David M, et al. “Developmental Abnormalities and Age-Related Neurodegeneration in a Mouse Model of Down Syndrome.” Proceedings of the National Academy of Sciences 93.23 (1996): 13333-38. Print.
[10]. Reeves, Roger H, et al. “A Mouse Model for Down Syndrome Exhibits Learning and Behaviour Deficits.” Nature genetics 11.2 (1995): 177-84. Print.
[11]. Davisson, Muriel T. “Segmental Trisomy of Murine Chromosome 16: A New Model System for Studying Down Syndrome.” Prog. Clin. Biol. Res. 360 (1990): 263-80. Print.
[12]. Pinter, Joseph D, et al. “Neuroanatomy of Down’s Syndrome: A High-Resolution Mri Study.” American Journal of Psychiatry 158.10 (2001): 1659-65. Print.
[13]. Davisson, Muriel T. “Segmental Trisomy of Murine Chromosome 16: A New Model System for Studying Down Syndrome.” Prog. Clin. Biol. Res. 360 (1990): 263-80. Print.
[14]. Abreu-Villaça, Yael, Cláudio C Filgueiras, and Alex C Manhães. “Developmental Aspects of the Cholinergic System.” Behavioural brain research 221.2 (2011): 367-78. Print.
[15]. Albright, Craig D, et al. “Choline Availability Alters Embryonic Development of the Hippocampus and Septum in the Rat.” Developmental Brain Research 113.1-2 (1999): 13-20. Print.
[16]. Lauder, JM, and UB Schambra. “Morphogenetic Roles of Acetylcholine.” Environmental health perspectives 107.suppl 1 (1999): 65-69. Print.
[17]. J Strupp, Barbara, et al. “Maternal Choline Supplementation: A Potential Prenatal Treatment for Down Syndrome and Alzheimer’s Disease.” Current Alzheimer Research 13.1 (2016): 97-106. Print.
[18]. Driscoll, Lori L, et al. “Impaired Sustained Attention and Error-Induced Stereotypy in the Aged Ts65dn Mouse: A Mouse Model of Down Syndrome and Alzheimer’s Disease.” Behavioral Neuroscience 118.6 (2004): 1196. Print.
[19]. Moon, Jisook, et al. “Perinatal Choline Supplementation Improves Cognitive Functioning and Emotion Regulation in the Ts65dn Mouse Model of Down Syndrome.” Behavioral neuroscience 124.3 (2010): 346. Print.
[20]. Yan, Jian, et al. “Maternal Choline Supplementation Programs Greater Activity of the Phosphatidylethanolamine N-Methyltransferase (Pemt) Pathway in Adult Ts65dn Trisomic Mice.” The FASEB Journal 28.10 (2014): 4312. Print.
[21]. Hunter, Christopher L, Heather A Bimonte, and Ann-Charlotte E Granholm. “Behavioral Comparison of 4 and 6 Month-Old Ts65dn Mice: Age-Related Impairments in Working and Reference Memory.” Behavioural brain research 138.2 (2003): 121-31. Print.
[22]. Granholm, Ann-Charlotte E, Linda A Sanders, and Linda S Crnic. “Loss of Cholinergic Phenotype in Basal Forebrain Coincides with Cognitive Decline in a Mouse Model of Down’s Syndrome.” Experimental neurology 161.2 (2000): 647-63. Print.
[23]. Holtzman, David M, et al. “Mouse Model of Neurodegeneration: Atrophy of Basal Forebrain Cholinergic Neurons in Trisomy 16 Transplants.” Proceedings of the National Academy of Sciences 89.4 (1992): 1383-87. Print.
[24]. Cooper, Jonathan D, et al. “Failed Retrograde Transport of Ngf in a Mouse Model of Down’s Syndrome: Reversal of Cholinergic Neurodegenerative Phenotypes Following Ngf Infusion.” Proceedings of the National Academy of Sciences 98.18 (2001): 10439-44. Print.
[25]. Prasher, Vee P, et al. “A 24‐Week, Double‐Blind, Placebo‐Controlled Trial of Donepezil in Patients with Down Syndrome and Alzheimer’s Disease—Pilot Study.” International Journal of Geriatric Psychiatry 17.3 (2002): 270-78. Print.
[26]. Ness, Seth, et al. “Down’s Syndrome and Alzheimer’s Disease: Towards Secondary Prevention.” Nature Reviews Drug Discovery 11.9 (2012): 655-56. Print.