An Extra Dose Of Amyloid
One of the genes on chromosome 21 codes for the Amyloid Precursor Protein , which is chopped up inside the brain to make the protein, amyloid. A build-up of amyloid in the brain is one of the hallmark features of Alzheimers, and while its still unclear exactly how amyloid contributes to the disease, its the focus of much research into new treatments.
Its thought that because people with Downs syndrome get an extra dose of APP, they can develop an excess of amyloid in the brain. This appears to make them much more likely to develop Alzheimers than someone without Downs syndrome and at an earlier age.
Despite this, not all people with Downs syndrome will develop Alzheimers and understanding why some people dont is another important avenue for investigation.
The unique genetic cause of Downs syndrome makes it an important condition to study to help unravel the causes of Alzheimers and help those affected by both conditions.
What Will They Do
This unique project is using state-of-the-art brain scanning to track the development of Alzheimers in a group of people with Downs syndrome, uncovering when the disease starts and how it progresses.
Recent advances in a form of brain imaging PET scanning now allows researchers to visualise the early build-up of the hallmark Alzheimers proteins amyloid and tau in the brain.
The team is also using MRI scanning to look for changes in brain structure.
They are tracking these changes in a group of people with Downs syndrome who are between 35 and 50 the time at which Alzheimers changes are thought to be starting in the brains of people with Downs syndrome.
The team can also study how these changes correlate with the start of Alzheimers symptoms such as memory loss, confusion and personality change.
The findings from this study have the potential to shed light on a critical period in the disease for preventative treatment in people with Downs syndrome, as well as providing insight that could benefit people with Alzheimers disease in the wider population too. Clinical trials of new medicines in people with Downs syndrome are likely to pave the way for more widespread clinical testing in the Alzheimers population as a whole.
The Importance Of Living A Full Life
Currently, there is no way to prevent the brain changes that may occur in people with Down syndrome. However, leading as full, healthy and active a life as possible may help reduce the risk of developing dementia. This includes keeping up interests in work and recreation, friends and family, maintaining good health, diet and fitness, and having regular medical check-ups.
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What Are The Symptoms Of Alzheimer’s Disease In People With Down Syndrome
The symptoms of Alzheimers disease in people with Down syndrome may be different than those typically seen in others with Alzheimers disease. For example, in the early stages of the disease, memory loss may not be the first change noted. In fact, it may be difficult to notice symptoms of Alzheimers disease because of the already present limitations in memory and functioning in the person with Down syndrome. More often, the early changes seen in people with Down syndrome may be those affecting personality, behavior, and overall function.
More specifically, these symptoms may include:
- Less interest in hobbies and previously loved activities and events
- Increase in irritability, agitation, aggressiveness, sadness, anxiety
- Loss of previously mastered skills
- Changes in sleep pattern, more restlessness
- Lowered attention span loss of concentration
- Increase in compulsions
Alzheimer’s Disease In People With Down Syndrome
Many but not all people with Down syndrome develop Alzheimers disease when they get older.
People with Down syndrome are born with an extra copy of chromosome 21, which carries a gene that produces a specific protein called amyloid precursor protein . Too much APP protein leads to a buildup of protein clumps calledbeta-amyloid plaquesin the brain. The presence of beta-amyloid plaques is one of the hallmarks of Alzheimer’s disease.
This type of Alzheimers in people with Down syndrome is not passed down genetically from a parent to a child.
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Why Are People With Down Syndrome At Greater Risk For Developing Alzheimers Disease
Scientists believe the increased risk is due to the extra chromosome, chromosome 21, that causes Down syndrome. Persons born with Down syndrome have three copies of this chromosome. Scientists have identified several genes on chromosome 21 that are responsible for certain aspects of the aging process. They believe the extra full or partial chromosome contributes to the increased risk of Alzheimers disease seen in people with Down syndrome. In addition, genes on chromosome 21 produce a key protein, amyloid precursor protein, which plays an important role in the brain changes that are specifically seen in Alzheimers patients.
Relationship Of Cognitive Ability To Brain Anatomy
In the AD population, there was a positive correlation between MMSE and corrected hippocampal volume and between MMSE and corrected temporal lobe volume . There was a negative correlation between MMSE and the corrected lateral ventricle volume . The DS+ population showed a positive correlation between CAMCOG and the corrected hippocampal volume and between CAMCOG and the corrected temporal lobe volume . There was a negative correlation between MMSE and the corrected lateral ventricle volume .
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What Treatments Are Available For Treating Alzheimers Disease In A Person With Down Syndrome
There are no specific drugs approved to treat the co-existing conditions of Alzheimers disease and Down syndrome. Two drug types are available to treat Alzheimers disease — the cholinesterase inhibitors and the NMDA receptor antagonist memantine . Unfortunately, there is not much evidence to support the use of either class in patients with both conditions. Theres not enough scientific evidence to conclude that the cholinesterase inhibitors are helpful in patients with Down syndrome and memantine has shown no benefit in these patients in a large clinical trial.
Several drugs that target some of the genetic and chemical changes in the brain that occur in people with Down syndrome and Alzheimers disease are currently being examined in very early clinical trials. Although scientists are generally encouraged by these early results, many more years of testing will be needed before these drugs may come to market and/or will be recommended for use in these patients.
Last reviewed by a Cleveland Clinic medical professional on 11/09/2018.
References
Potential Difficulties In Making A Diagnosis
The clinical picture of Alzheimer’s disease in Down’s syndrome is complex, owing to the pre-existing cognitive impairment and atypical presentation. Difficulties with making a psychiatric diagnosis in a person with Down’s syndrome include psychosocial masking. This refers to the unsophisticated social skills and lack of life experiences that a person with learning disability might exhibit, which can alter the presentation of symptoms. People with Down’s syndrome may not present their symptoms verbally, because of their impaired communication skills. In fact, carers might be more likely to highlight a change than would the person with Down’s syndrome.
Diagnostic overshadowing means the attribution of changes in behaviour or ability to learning disability. For people with Down’s syndrome, diagnostic overshadowing can mean that they are referred to specialist services late or not at all. When learning disability is present, diagnostic overshadowing seems to reduce the significance attached to abnormal behaviour which might otherwise have been attributed to psychiatric disorder. In addition, some abnormal behaviours may be seen as less significant than the learning disability itself. Taken to its fullest extent, the behaviour may be attributed solely to the intellectual impairment, rather than to a psychiatric disorder such as dementia.
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What Is Down Syndrome Dementia
Down syndrome is a condition characterized by the presence of extra material on chromosome 21. People living with Down syndrome have an increased risk of developing dementia as they get older. Dementia associated with Down syndrome is thought to be very similar to traditional forms of Alzheimers disease.
More than 75 per cent of people with Down syndrome aged 65 and older are living with Alzheimers disease, about six times the number of people in the greater population in the same age group. The risk of developing Alzheimers disease in individuals with Down syndrome has been found to increase with advancing age.
Since people with Down syndrome typically live up to 55-65 years of age, they are more likely to have young-onset Alzheimers disease rather than the classical type that affects individuals older than 65 years.
People with Down syndrome have been found to have significant levels of plaques and tangles in brain nerve cells a common feature of Alzheimers disease appearing by the age of 40. Surprisingly enough, not everyone with these brain changes develops symptoms of Alzheimers disease. It is not known why some people with Down syndrome who have brain changes develop symptoms – while others do not.
Alzheimers And Down Syndrome Research Highlight
One ABC-DS study found disruptions in the way cells process and break down energy in people with Down syndrome who had Alzheimers or mild cognitive impairment. Researchers measured these metabolic changes in the blood and found that they increased based on disease stage. Findings suggest that measuring such metabolic factors could be a potential way to track the disease.
In 2018, NIH launched the INCLUDE project to address health and quality-of-life needs for people with Down syndrome. Through INCLUDE-supported studies, researchers are exploring connections between Down syndrome and other conditions including Alzheimers, autism, cataracts, celiac disease, congenital heart disease, and diabetes.
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Assessment Of Alzeihmers Disease In People With Down Syndrome
Health professionals should do a baseline functional assessment annually from the age of 40 to assess and document changes. Carers or family should pass on information to the doctor about any changes they notice. Assessment should include the six domains:
- Cognition, memory and executive function
- Behaviour and personality
Brain Changes Associated With Alzheimers Disease
There is a complex connection between chromosome 21 and Alzheimer’s disease. The amyloid precursor protein , which is a part of the nerve fibre tangles that typically appear in Alzheimer’s disease, is localised on chromosome 21. Having three copies of the APP gene results in excess production of APP and may cause acceleration of the brain changes that typify Alzheimer’s disease in people with Down syndrome.
The mechanisms that trigger these brain changes are not yet fully understood, even though great steps have been made in research in this area. A current aim of research is to find a way to slow down the onset of these brain changes.
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What Is Down Syndrome
Down syndrome is a genetic disorder caused when, due to a biological error at the time of conception, a person has 3 copies of chromosome 21 in every cell body instead of the usual pair, so upsetting the gene balance. This extra gene material causes a collection of characteristics which can result in some degree of developmental delay and some common physical traits.
Clinical Trials And Translational Research
A 2015 literature-based review of randomized clinical trials of anti-dementia medications for adults with DS indicated that insufficient data exist to evaluate the therapeutic effects of acetylcholinesterases, memantine, simvastatin, antioxidants, and L-carnitine in this population223. Although most of the existing studies of anti-dementia therapies in DS were considered to be well conducted, the small number of participants and the outcome methodology employed did not enable results from different trials to be combined. Consequently, larger trials conducted over longer periods of time and that use uniform criteria are needed. In addition, if preventative interventions are to be tested, then biomarkers will be necessary that act as proxy indicators for disease progression 224. This point is also true for AD in the general population in those individuals who have a slow disease onset that allows consideration of preventative therapies 225.
Hypothetical progression of Alzheimer disease neuropathology in Down syndrome.
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Executive Function And Language
In one of the studies, executive dysfunction was investigated by looking at verbal intrusions as an indicator of disruption of inhibition control . Responding with an irrelevant word during a task of verbal memory retrieval was found to be predictive of performance on two out of three memory tasks administered within the next three years. Therefore, the authors argued that verbal intrusions are an early sign of Alzheimer-related neuropathology, preceding declines in memory. Interestingly, middle aged participants with DS made more verbal intrusions at baseline compared to participants with unspecified ID , giving further support to the idea that executive functioning is more sensitive to decline in DS than in other populations.
The Link Between Down Syndrome And Alzheimers Disease
Studies show that by the age of 40, almost 100% of people with Down syndrome who die have the changes in the brain associated with Alzheimers disease. Amyloid precursor protein , which is the abnormal breakdown that yields the toxic amyloid protein that forms plaques in the brain and probably damages brain cells and their connections, is coded for chromosome 21. Because people with Down syndrome have an extra copy of chromosome 21, they make 1.5 times as much APP as other people, and this seems to result in an excess tendency for the abnormal amyloid breakdown product to build up. This appears to cause earlier appearance of the brain changes typical of Alzheimers disease. However, a significant number of people with Down syndrome are older than 40 and show no signs of having Alzheimers disease. It is not currently understood why changes to the brain that are typical of Alzheimers disease do not necessarily produce the condition in people with Down syndrome.
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General Definition And Overview
Alzheimers disease is a type of dementia that gradually destroys brain cells, affecting a persons memory and their ability to learn, make judgments, communicate and carry out basic daily activities. Alzheimers disease is characterized by a gradual decline that generally progresses through three stages: early, middle and late stage disease. These three stages are distinguished by their general features, which tend to progress gradually throughout the course of the disease. Alzheimers disease is not inevitable in people with Down syndrome. While all people with Down syndrome are at risk, many adults with Down syndrome will not manifest the changes of Alzheimers disease in their lifetime. Although risk increases with each decade of life, at no point does it come close to reaching 100%. This is why it is especially important to be careful and thoughtful about assigning this diagnosis before looking at all other possible causes for why changes are taking place with aging. Estimates show that Alzheimers disease affects about 30% of people with Down syndrome in their 50s. By their 60s, this number comes closer to 50%.
Data Collection And Analysis
Selection of studies
Two authors independently reviewed titles and abstracts of references retrieved from the searches and selected all potentially relevant studies. Copies of these articles were obtained, and reviewed independently by the same authors against the inclusion criteria of the study.Authors were not blinded to the names of the trial authors, institutions or journal of publication. There was no disagreement between the authors and they did not approach or appeal to the editorial base of the Cochrane Developmental, Psychosocial and Learning Problems Group for consensus. No relevant reports of studies of rivastigmine were obtained. If updated searches retrieve any reports of studies which meet the inclusion criteria for this review, they will be analysed using the methods detailed in Appendix 10.
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What Are The Symptoms
In people living with Down syndrome, changes in overall function, personality and behavior may be more common as early signs of Alzheimer’s disease than memory loss. Early symptoms may include:
- Lack of interest in socializing, communicating or expressing thoughts
- Lack of initiative and enthusiasm for common activities
- Emotional changes such as sadness, fearfulness, anxiety or irritability
- Behavioural changes including aggression, restlessness or sleep disturbances
- Seizures that begin in adulthood
- Changes in coordination and walking
- Increased noisiness or excitability
Researchers are unclear as to why these symptoms differ for people with Down syndrome compared to the general population.
What Kind Of Changes Should I Follow Up On
In people with Down syndrome, the first signs noticed by family or carers may be changes in behaviour and personality, such as an increase in stubbornness or behaving inappropriately. Other early signs include difficulty with attention, and changes in planning, solving problems, and making judgements.
Other changes may be present such as social withdrawal, confusion, irritability, repetitive speech, or seizures for the first time in adulthood.
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Description Of The Condition
Dementia in Down syndrome
The most common genetic disorder recognised at birth is Down syndrome . This is caused by the presence of all or part of an extra copy of chromosome 21, which can lead to deficits in areas of assimilation and adaption along with cognitive impairment. Alzheimer’s disease is a degenerative disease, clinically manifesting as a progressive dementia with a loss of global functioning and cognitive abilities. It is characterized by an increase in amyloid plaques and neurofibrillary tangles in the brain, and reduced levels of cerebral cortical levels of acetylcholine . There are well established and recognised neuropathological and neurochemical links between DS and AD with both associated with chromosome 21 . In Down Syndrome this additional chromosome can lead to fewer neurons and lower levels of acetylcholine as compared to the general population. Research suggests that cholinergic deficits have been linked to the loss of neurons in the nucleus basalis of Meynert in patients with AD and also with people who have DS. .
Assessing and monitoring dementia in people with Down syndrome
To mention a few which are administered to the informant/carer:
Of those tests administered to people who have little or no speech, the Test for Severe Impairment assesses short and long term memory, motor skills, language, conceptualisation, general knowledge and the Spatial Recognition Span assesses immediate spatial recognition .