Genes Associated With Risk In Sporadic Ad
AD2: APOE
Inheritance and clinical features
The APOE gene has been associated with both familial late-onset and sporadic late-onset AD in numerous studies of multiple ethnic groups. The APOE4 genotype is associated with higher risk of AD, earlier age of onset of both AD and Down syndrome , and a worse outcome after head trauma and stroke, both in humans and in transgenic mice expressing human APOE4. The frequency of the APOE4 allele varies between ethnic groups, but regardless of ethnic group, APOE4 carriers are more frequently found in controls and APOE4+ carriers are more frequently found in patients with AD.,
Gene location and structure
Apolipoprotein E structure and single nucleotide polymorphisms . The general protein structure of APOE is shown. The 2 SNPs in exon 4 and corresponding protein locations are shown . The 3 APOE 4 alleles are defined by 2 SNPs, rs429358 and rs7412, with 2 defined by nucleotides T-T 3 defined by T-C, and 4 defined by C-C, respectively.
Gene function and expression
The mechanisms that govern apoE toxicity in brain tissue are not fully understood. Some proposed mechanisms include isoform-specific toxicity, APOE4-mediated amyloid aggregation, and APOE4-mediated tau hyperphosphorylation.
In addition, individuals carrying APOE4 have higher amyloid and tangle pathology and an increase in mitochondrial damage compared to those carrying other APOE polymorphisms.
Genetic variation
Testing For Familial Alzheimers Disease
The decision to undergo testing for FAD is very complex and the advantages and disadvantages must be carefully considered. The test does not produce a relative risk of acquiring the dementia, but is a definitive prediction of whether a person will get a profound and progressive illness in ones middle years. The test can only be completed with the informed consent of the person being tested. No one should ever be pressured to have such a test.
Knowing that you are carrying the gene may help some people plan for the future. It enables them to consider future lifestyle choices and to let their wishes be known to someone they trust. However, given that no cure is available an individual has to consider whether they want to know that they will develop dementia at some time in the future.
To help people consider these issues specialised genetic counselling is essential. The doctor can provide details of this service. In the future, when preventive treatments for Alzheimers disease become available, there may be increased reasons to seek testing.
What Is A Gene Variant
The same gene can differ between individuals these are known as gene variants. These can help to explain why people are different to each other for instance, why one person has blue eyes and another person has brown eyes.
If a gene variant increases a person’s risk of developing a disease, it is known as a ‘risk variant’ for that disease.
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Genes: A Blueprint For Health And Disease
The genes encoded in our DNA are profoundly involved in many aspects of our health. They act as a sort of blueprint for the construction, operation, and repair of our bodies throughout life. Genes provide instructions for the creation and regulation of our bodys building blocks. We inherit one copy of each gene from each of our parents, which is one reason why every person has a unique appearance and metabolism.
The effects of a gene can be dramatically changed by mutation of even one pair of its molecules. Specific versions of genes, called alleles, are passed down through a familys lineage, potentially creating an entire population of people who share a healthy characteristic such as resistance to cancer a more neutral characteristic such as eye color or a heightened risk for a specific disease such as Alzheimers disease .
Many of us have learned about Mendel, who was an Austrian monk, and the pea plants he bred as he discovered basic principles of genetic inheritance. Just as with Mendels plants, some physical characteristics can be transmitted to our offspring through inheritance of even one version of a gene. Many diseases are inherited this way, too.
Are There Harms Or Limitations Of Genetic Testing
Currently no cure or effective preventive therapy is available if a gene mutation is found. A positive test result for a known early-onset familial AD family gene mutation can result in:
- Adverse psychological reaction, family issues/distress
- Confidentiality issues
Insurance discrimination
- Historically, genetic testing in an asymptomatic individual may have affected their ability to obtain life, disability, critical illness, long-term care and/or extended health insurance. However, in 2017 Canada passed the Genetic Information Non-Discrimination Act that protects individuals from the use of a genetic test result to prevent them from obtaining insurance.
A negative test result for a known familial early-onset familial AD gene mutation can result in survivor guilt.
When an individual with no known familial gene mutation has genetic testing, a negative result is not a definitive answer.
For review articles on AD see Alonso Vilatela ME et al., Genetics of Alzheimers disease. Arch Med Res. 2012 43: 622-31 and Goldman JS et al., Genetic counseling and testing for Alzheimer disease: Joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genet Med 2011 13: 597-605.
Other AD resources:
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What Are The Types Of Genetic Disease
There are many types of genetic diseases. Four of the main types are:
Single gene inheritance diseases are diseases that occur because one defective gene is present. They are known as monogenetic disorders. There are thousands of known single gene inheritance diseases, and they may be inherited in different ways. Autosomal dominant inheritance means that only one copy of the defective gene must be present to cause the condition. Autosomal recessive diseases require that an affected person receive a defective copy of the gene from each parent. X-linked disorders refer to diseases for which the defective gene is present on the female chromosome.
Examples of single gene inheritance disorders include:
When To See A Doctor
Seeking medical assistance for a person who demonstrates these symptoms is vital, even though the discussion might be a difficult one. A doctor can rule out other diseases that might cause dementia, such as a urinary tract infection or brain tumor.
Before an appointment, family members should make a list of any medications the person with symptoms is currently taking. The doctor can review the list and make sure dementia symptoms are not side effects of current medications.
Keep a journal of noticeable symptoms as they develop over time to help a doctor establish potential patterns.
Although genetic testing that can detect the genes that have links to Alzheimers disease is available, doctors do not generally recommend this testing for late-onset diseases.
The presence of the genes does not necessarily mean that a person will have the condition. Testing could cause unnecessary worry, anxiety, and fear.
However, a person with a family history of early-onset Alzheimers may wish to pursue genetic testing. Most doctors will recommend meeting with a genetic counselor beforehand to discuss the pros and cons of genetic testing, and how they can interpret the results.
Sometimes, a doctor may recommend genetic testing when people show early Alzheimers symptoms, as this may dictate possible treatments and potential for therapeutic drug trials.
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What Is Alzheimer’s Disease
Alzheimer’s is a disease that causes dementia, or loss of brain function. It affects the parts of the brainthat are important for memory, thought, and language.
The brain of a person with Alzheimer’s contains abnormal clumps of cellular debris and protein and collapsedmicrotubules . Microtubule collapse is caused by a malfunctioning protein calledtau, which normally stabalizes the microtubules. In Alzheimer’s patients, tau proteins instead cluster together to formdisabling plaques and tangles. These plaques and tangles damage the healthy cells around them, leading to cell death. The brain also producessmaller amounts of neurotransmitters ,chemicals that allow nerve cells to talk to one another.
The most common form of the disease, which strikes after age 65, is linked to the apolipoprotein E gene on chromosome 19.Scientists don’t know how apoE4 increases the risk of developing Alzheimer’s. They do know that everyone has apoE, which comes in three forms.
One of the forms increases a person’s risk of developing Alzheimer’s.The other two forms seem to protect against the disease. While people who inherit the apoE4 form of the geneare at increased risk for the disease, they will not necessarily develop it.
Mutations in genes found on chromosomes 1, 14, and 21 are linked to rarer forms of the disease, which strike earlier in life.
How Is Alzheimer’s Disease Treated
There is no cure for Alzheimer’s, but a few medicines can slow its symptoms. A drug called Aricept increases the amount of the neurotransmitter acetylcholine in the brain. Another medicine, Namenda, protects brain cells from a chemical called glutamate, which can damage nerve cells. Doctors may also give their Alzheimer’s patients antidepressants or anti-anxiety medicines to ease some of their symptoms.
People with Alzheimer’s often need a caregiversomeone to help them do thethings they were once able to do themselves.
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Support For Family And Friends
Currently, many people living with Alzheimers disease are cared for at home by family members. Caregiving can have positive aspects for the caregiver as well as the person being cared for. It may bring personal fulfillment to the caregiver, such as satisfaction from helping a family member or friend, and lead to the development of new skills and improved family relationships.
Although most people willingly provide care to their loved ones and friends, caring for a person with Alzheimers disease at home can be a difficult task and may become overwhelming at times. Each day brings new challenges as the caregiver copes with changing levels of ability and new patterns of behavior. As the disease gets worse, people living with Alzheimers disease often need more intensive care.
You can find more information about caring for yourself and access a helpful care planning form.
What Is Known About Alzheimers Disease
Scientists do not yet fully understand what causes Alzheimers disease. There likely is not a single cause but rather several factors that can affect each person differently.
- Age is the best known risk factor for Alzheimers disease.
- Family historyresearchers believe that genetics may play a role in developing Alzheimers disease. However, genes do not equal destiny. A healthy lifestyle may help reduce your risk of developing Alzheimers disease. Two large, long term studies indicate that adequate physical activity, a nutritious diet, limited alcohol consumption, and not smoking may help people. To learn more about the study, you can listen to a short podcast.
- Changes in the brain can begin years before the first symptoms appear.
- Researchers are studying whether education, diet, and environment play a role in developing Alzheimers disease.
- There is growing scientific evidence that healthy behaviors, which have been shown to prevent cancer, diabetes, and heart disease, may also reduce risk for subjective cognitive decline. Heres 8 ways.
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If Familial Alzheimers Disease Is Suspected
Genetic testing can identify specific changes in a persons genes. This test can tell if a person has FAD and if a child has inherited the changed gene from a parent and will develop the disease in the future. It cannot determine when the symptoms will begin. It is essential to ensure that suspected cases in the family have, or have had, Alzheimers disease and not some other form of dementia. This can only be done through a medical examination, or a careful analysis of past medical records if the person is no longer alive.
Dementia Caused By A Complex Disease
Nearly all cases of dementia are the result of a complex disease. In these cases, genes may increase the risk of developing dementia, but they dont cause it directly.
What causes complex disease dementias?
When dementia is the result of a complex disease, it is likely to be caused by a combination of risk factors. These include:
- non-genetic factors for example, members of the same family may all smoke or have an unhealthy diet, which are both risk factors for dementia.
- genetic factors a person may inherit the same dementia risk variants as other members of their family. This could include variants in genes such as APOE.
These factors are often shared by members of the same family. This is why many people have some family history of dementia for example, they may have a parent who developed dementia in their 90s and a brother who developed dementia in his 70s. This is not the same as familial dementia.
Is it possible to directly inherit dementia when it’s caused by a complex disease?
No. People who are related to each other by birth are more likely to have the same risk variants as each other. However, risk variants for dementia do not directly cause dementia . This means that its not possible to directly inherit dementia through risk variants.
However, a person who has dementia risk variants is at higher risk of developing dementia than someone who does not have risk variants. Despite this higher risk, they still might not develop dementia.
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Other Rare Types Of Dementia
Other rare types of dementia that can be passed down through the family include Huntingtons disease and Familial Prion disease. These diseases have a 50/50 chance of being passed on because they are caused by a single faulty dominant gene.
This means that, if you inherit a healthy gene from one parent and a faulty gene from the other parent, the faulty one will always be the one that is used because its the dominant gene.
For more information, care and support services, please refer to the Huntingtons Disease Association or the National Prion Clinic at UCL.
What Is The Burden Of Alzheimers Disease In The United States
- Alzheimers disease is one of the top 10 leading causes of death in the United States.2
- The 6th leading cause of death among US adults.
- The 5th leading cause of death among adults aged 65 years or older.3
In 2020, an estimated 5.8 million Americans aged 65 years or older had Alzheimers disease.1 This number is projected to nearly triple to 14 million people by 2060.1
In 2010, the costs of treating Alzheimers disease were projected to fall between $159 and $215 billion.4 By 2040, these costs are projected to jump to between $379 and more than $500 billion annually.4
Death rates for Alzheimers disease are increasing, unlike heart disease and cancer death rates that are on the decline.5 Dementia, including Alzheimers disease, has been shown to be under-reported in death certificates and therefore the proportion of older people who die from Alzheimers may be considerably higher.6
Aging
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Genetic Causes Of Dementia
One rare form of Alzheimers disease is passed from generation to generation. This is called Familial Alzheimers disease . If a parent has a mutated gene that causes FAD, each child has a 50% chance of inheriting it. The presence of the gene means that the person will eventually develop Alzheimers disease, usually in their 40s or 50s. This form of Alzheimers disease affects an extremely small number of people probably no more than 100 at any given time among the whole population of Australia.
Three genes have been identified which, if mutated in certain ways, will cause FAD. These are called presenilin 1 , presenilin 2 and the amyloid precursor protein gene on chromosome 21.
Genes And Vascular Dementia
Vascular dementia is caused when blood flow to the brain is reduced, damaging nerve cells. This can happen as a result of a stroke or damage to blood vessels deep in the brain. The majority of cases of vascular dementia are not caused by faulty genes.
We may carry genes that affect our risk of stroke, heart disease or other diseases that may contribute to vascular dementia. However, lifestyle factors such as smoking, lack of exercise, obesity, drinking alcohol over the recommended limits, and an unbalanced diet can also affect our risk.
There are rare genetic disorders that can cause vascular dementia by damaging blood vessels in the brain. One is called CADASIL and can be passed down through families. CADASIL only affects around 1,000 people in the UK.
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How Do People Get Alzheimer’s Disease
Scientists don’t know exactly how people develop Alzheimer’s, but they believe it is caused by a combination ofgenes and environmental factors. In other words, it is a multifactorial disorder.
The early-onset forms of Alzheimer’s are inherited in an autosomal dominant pattern, which means that only one parenthas to pass down a defective copy of the gene for their child to develop the disorder.
Genetic Testing And Counseling
In contrast, EOFAD, with an age at onset before 60 to 65 years old, has an autosomal dominant mode of inheritance in which 20% to 70% of cases are estimated to have a PSEN1 mutation, 10% to 15% of cases are estimated to have an APP mutation, and PSEN2 mutations are rare., Indeed, approximately 60% of patients with EOAD have another known affected family member. The remaining 40% of patients with EOAD may lack a family history because of an early death of a parent, failure to recognize the disorder in family members, or, very rarely, a de novo mutation. If the parent of a patient with EOAD has a mutant allele, then the risk to the patients sibling of inheriting the mutant allele is 50%. The child of a patient with EOAD who carries a mutation has a 50% chance of transmitting the mutant allele to each of their children.
In this article, we have reviewed the genetics of AD. Further molecular genetic investigations should clarify the roles of additional known genes in the pathogenesis of both common sporadic as well as rare familial forms of AD. Already, investigations of the normal and aberrant functions of A protein and ApoE has provided insight into the underlying mechanisms for AD. Such research will continue to provide new strategies for therapeutic interventions.
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