1.0 Introduction
Down syndrome (DS) is a genetic condition caused by trisomy 21 (the presence of three copies of chromosome 21 rather than two). Although the actual cause of Down syndrome remains unknown, several risk factors increase the chances of a baby being born with the disorders. The primary risk factor, is the maternal, with about 80% of the cases of Down syndrome occurring in babies born by women above the age of 35. Other risk factors are genetic predisposition (indicated by siblings, another baby or parent with Down syndrome), immunologic problems, hormonal abnormalities, viral infection or x-rays. The risk factors are thought to result in abnormal cell division (meiosis) that leads to an extra copy of chromosome 21. The disorder is the most common cause of mental retardation and is associated with mild to severe intellectual disability, developmental delays and some physical disabilities. It is therefore classified as a genetic mental disorder affecting intellectual capabilities. Down syndrome occurs in one out of every 733-800 live births in the U.S and Canada.
Although Down syndrome has some common characteristics each person with the disorder different health complications. The common features of Down syndrome are: weak muscle tone (hypotonia); short, stocky arms and legs (one or both palms may have a single crease, the big toe and the second toe are often widely spaced); shorter stature than averages with children growing very slowly; extremely flexible joints (hyperflexibility) and short and wide neck supporting a disproportionately small head. The disorder also has characteristic facial features such as slanted eyes, flat nasal bridge; small and irregularly shaped oral and tongue; small ears and crooked teeth that come in late. In addition, the disorder is associated with increased incidences of health problems like heart defects, autism, leukemia, Attention deficit hyperactivity disorder (ADHD), intellectual disability, depression, Hypothyroidism, eye conditions, celiac disease and early-onset Alzheimer’s disease. This paper will particularly review the link between Down syndrome and Alzheimer’s disease.
2.0 Alzheimer’s disease
Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disorder that is associated with progressive degeneration of the neurons (particularly in the brain) leading to the impairment of memory and cognitive functions (Abisambra, Fiorelli, Padmanabhan, Neame, Wefes, & Potter, 2010; Nd; University of British Columbia , 2011; National Down Syndrome Society, 2012). The degeneration of the brain functions progressively impairs the normal daily functions and activities of a person in three stages. The initial stage of the disease is associated with decline in short term memory, difficulties in planning, reduced work productivity, spatial disorientation, difficulties in learning new information, depression, decline in fine motor regulation, language, dyspraxia, personality and behavior changes. The intermediate stage mainly affects ability to express emotions appropriated, judgment, causes mood swings, disorientation in time and space, ability to recognize familiar places, objects and people. The third and final stage of Alzheimer’s disease is associated with major deterioration doing the normal daily activities. The last stage causes inability to communicate, inability to move, impaired chewing and swallowing mechanism, marked intellectual deterioration and thus the individual with Alzheimer’s disease requires complete care.
Alzheimer’s disease often affects people in their old age although it is not an inevitable part of normal aging (Alvarez, Nd). It is the commonest form of dementia in people over the age of 60. In a majority of the cases (95% 0f the cases) the symptoms of the disorder appear at the age of 65 and the incidences increase with age (almost half of the population over 85 years age are affected by AD).
3.0 Incidences of Alzheimer’s disease in Down syndrome patients
The link between Down syndrome and Alzheimer’s disease, based on genetic studies, clinical and pathological observations, has been acknowledged and documented for decades (Desai, nd). A majority of the people with Down syndrome develops similar changes in the brain as those observed in Alzheimer’s disease and thus they may display similar behavioral changes (Alvarez, Nd). About twenty years ago, this similarity in brain changes led to a notion that the two mental disorders are the same; a notion that raised a lot of controversy. However, the two disorders are distinct and can occur either independently or together. While Alzheimer’s disease sets in at an advanced age, Down syndrome is a disorder that people are born with. Never the less the prevalence of Alzheimer’s disease has been reported to be 3-4 times more than in the general population (Alzheimer Society of Canada, 2010; Better Health channel , 2011; Alvarez & Hoffmann, 2012; Glass, 2012).
4.0 The connection between AD and DS
The pathophysiology of AD is characterized by deposition/accumulation of β-amyloid (a toxic protein resulting from an abnormality in the metabolism of amyloid precursor protein-APP) in the brain and walls of the blood vessels, neuroinflamation and intraneuronal neurofibrillary tanges. These processes, and particularly the formation of plaques in the brain, result in the loss of neurons hence the progressive dementia (Alvarez, Nd). The loss of the brain cells is as a result of damages to the cells by the toxic β-amyloid. Two enzymes mediate the abnormal metabolism of APP: γ- and β-secretase. At the genetic level, the amyloid deposition is a result of mutations in the APP gene (resulting in increase or changes in Aβ, a 38–42 amino acid peptide) and presenilin (PS) genes that code for the catalytic site of γ- secretase.
One of the major links between AD and DS is the presence of increased levels β-amyloid and the consequent senile plaques in DS patients between the age of 30 and 40. As earlier mentioned, senile plaques are the hallmarks of the pathophysiology of Alzheimer’s disease. Since the gene that encodes APP (the precursor of β-amyloid) is located in chromosome 21, it is postulated that the over expression of this gene in DS patients (who have 3 copies of chromosome 21) is responsible for the increased levels of the toxic APP metabolite (β-amyloid). However, studies with mice indicate that over expression of this gene alone does not precipitate into Ad pathological symptom. This implies that there may be other genes, albeit in chromosome 21, that are responsible for the AD pathological observations. Ryoo et al., (2008) identified various protein molecules that are involved in the pathophysiology of AD and located the genes encoding these proteins on chromosome 21. Thus trisomy 21 not only leads to an increase in the production of APP and consequently β-amyloid, but also results in the over expression of other proteins involved in the pathophysiology of AD .
Another finding relating to senile plaque observed in AD patients with DS is the higher levels of the γ- and β-secretase in people with DS. As earlier mentioned these enzymes play a crucial role in metabolism of APP to beta amyloid protein by catalyzing the cleavage of APP. Beta site APP-cleavage enzyme 1 (BACE1), is one of the most vital secretase enzyme that is elevated in DS. This particular enzyme has been found in DS patients as young as 8 years old (Alvarez & Hoffmann, 2012).
Another gene that has been implicated in the pathophysiology of AD and that is located on chromosome 21 is SOD-1 gene. This gene encodes for superoxide dismutase (SOD-1), the cytoplasmic enzyme that mediates the regulation of reactive oxygen species (ROS) such as hydrogen peroxide, hydroxyl radical, superoxide anions and nitric oxide that are potentially toxic to the cells. The over expression of the SOD-1 gene leads to increased activity of SOD-1 which in turn leads to the accumulation of ROS in different body cells including erythrocytes, lymphocytes, fibroblasts and brain cells. The ROS accumulate to toxic levels leading to the cell death (of particular interest in AD is neuronal death), impaired immunological function and carcinogenesis (Alvarez & Hoffmann, 2012). Under normal circumstances of the production of ROS and removal is intricately balance and thus the cells are not damaged. An imbalance in the ROS production and removal has been linked to increased oxidative stress that leads to damages in the cellular membranes and DNA, which releases more products that are toxic (Alvarez & Hoffmann, 2012).
According to a study conducted by scholars at the University of British Colombia, one of the proteins that is over expressed in people with DS is the Regulator of Calcineurin 1 (RCAN1). The said protein sets in motion a cascade of events that result in apoptosis (cell death) of neurons in the cortex and hippocampus. The loss of the neurons is the main culprit in the memory loss and other cognitive impairments that have been associated with AD and hence the connection between AD and DS. The study postulated that the presence of an extra copy of chromosome 21 in DS results in the over expression of the gene responsible for RCAN1 and that the consequent neuronal death is one of the primary causes of the reduced lifespan of DS patients. However, the study also found high levels of the protein in AD patients with two copies of the RCAN1 gene (i.e AD patients without DS). In this cases, the researchers attribute the over production of RCAN1 to other factors like stroke and the presence of beta amyloid that trigger the vicious cycle culminating in neuronal apoptosis .
Another common characteristic of AD and DS is the presence of chromosome 21. One study found that patients of AD have some cells with 3 rather than 2 copies of chromosome 21. Conversely, DS patients have trysomy 21 in all cells. It is this discovery that led to the somewhat controversial conclusion that AD could be a late onset form of DS.. Apparently, the beta amyloid (resulting from the over expression of APP) in DS patients disrupts the network of microtubules that facilitate the distribution of duplicated chromosomes during cell division. The disrupted microtubules network in turn leads to the incorrect distribution of chromosomes during cell division and thus leading to the abnormal number of chromosomes in the cells. As such, the events leading to increased AD in DS patients are intricate and complex. The presence of trysomy 21 in DS patients means that they have three copies of the APP gene. This leads to the accumulation of beta amyloid protein, which in turn leads to more disruption of the microtubules and more aneuploidy. This probably accounts for the ever-increasing number of nerve cells with trisomy 21 in AD.
Another study also reported the damage of microtubule by amyloid protein and further consequences that implicate DS as a risk factor for AD. As earlier mentioned, AD is also associated with formation of plaque in the blood vessels which is as a result of increased amyloid proteins. The increased amyloid proteins in DS patients damages the network cellular microtubules making the cellular receptors that retrieve low-density lipoprotein (LDL) from the blood vessels to have difficulties in reaching the cell surface. This results in the accumulation of LDL in the blood vessels, which in turn reduces blood supply to the heart and the brain. The deficient blood supply to the brain could contribute to the loss of neurons in the brain and the subsequent memory and learning impairments that are observed in DS and AD. The reduced movement of other molecules such as the brain-signaling molecule and the insulin receptors also contribute to the pathophysiology of AD because these molecules promote proper memory and learning processes.
There are also structural and functional deficiencies in DS that predispose the patients to AD. Autopsy studies indicate people with DS have smaller brain size, reduced number and depth of cerebral sulci, norrower superior gyrus and a lighter brain. These changes in the brain may play a role in early onset of AD in people with DS. The other changes that indicate the connection between AD and DS are cognitive changes. Brain imaging studies have shown that people with diminished baseline cognitive abilities are at a higher risk of getting AD. As such, because DS is associated with diminished cognitive abilities people with DS are at a higher risk of developing AD, this is what is referred to as cognitive reserve hypothesis (Alvarez & Hoffmann, 2012).
5.0 Prevention and Treatment of AD
Currently there is no cure or proven preventive strategy for AD. However, there is a myriad of ongoing research on prevention strategies that is fairly promising. The available data indicate that prevention strategies employed in cardiovascular diseases goes a long way in preventing AD. Such measures include maintaining a healthy weight through exercise and a healthy diet, a low cholesterol diet, social engagement and memory stimulation exercises. There are also ongoing studies that point to the use of anti-inflammatory drugs and estrogen replacement as preventative strategies. Other ongoing trials pointing to the use of antioxidants and cholinergic agonists could improve cognitive functions. Other prevention strategies being reviewed include studies of antihypertensive agents, conjugated estrogen, pravastatin, rofecoxib, simvastatin, raloxifene and CX516 (AMPA agonist).
Currently there is no cure for AD and thus the disorder can only be managed by strategies that will slow down the progression of the disorder. Some of the drugs used to manage AD include memantine, galantamine, donepezil and rivastigmine. There is evidence that vitamin B complex and vitamin E could slow down the progression of the disease.
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