What Are Your Alzheimer’s Risk Factors If Your Parent Has the Disease?

How likely will one have Alzheimer’s Risk Factors with parental history? A lot of us are burdened by this question when our family member is diagnosed with this debilitating disorder. Having a parent with Alzheimer does not predispose you to develop this disease, but it does not rule out the possibility of getting it. Research suggests that persons whose parent or sibling has Alzheimer disease are more susceptible to developing Alzheimer disease as compared to others who do not have the disease.

Does it mean Alzheimer is hereditary or is it genetic? The answer is complex. The family history is in fact the second best predictor of Alzheimer disease after old age. Twin and family studies suggest a genetic impact in at least 80 percent of cases of Alzheimer. Nevertheless, there are only a few, less than five percent, cases of inherited or familial Alzheimer disease. Moreover, scientists have also discovered over 70 genes that can contribute to the risk of getting Alzheimer disease. The APOE-e4 gene has been identified as one of the major genetic contributors to Alzheimer, and researchers estimate that the gene is found in 40-65% of individuals diagnosed with Alzheimer, but only about 2% of the U.S. population carries two copies of this gene.

In this article, we will address the difference between inherited and sporadic Alzheimer, genes which directly cause the disease, risk factors which predispose the disease, and provide recommendations on genetic testing and preventive steps in individuals at increased risk.

Inherited vs Sporadic Alzheimer’s: What’s the Difference?

The distinction between a hereditary and a sporadic case of Alzheimer disease will help explain your own risk in the event that a parent has been diagnosed. These two different groups are the reason why there are multiple cases in some families and one-off cases in others.

Is Alzheimer’s risk factors hereditary or genetic?

The response is subtle- Alzheimer disease has both a genetic and a hereditary component but the terms are not interchangeable. There is all hereditary Alzheimer and genetic but not all genetic Alzheimer is hereditary.

The differences in the DNA that influence the development of diseases are the genetic factors. These differences are found in your genes whether you know a member of your family that has contracted the condition or not. Hereditary in its turn particularly defines the conditions directly traced back by their parents and passed on through generations.

There are two broad categories of alzheimer disease:

1.            Late-onset Alzheimer (sporadic): This is the most common, and is generally acquired at age 65 or older.

2.            Early-onset Alzheimer: Rare, between ages 30-65, and a sub-group of this is familial (hereditary).

Genetics contributes to each of the two situations (but to varying extents). When individuals pose this question, is Alzheimer passed on by mother or father? they are generally referring to hereditary Alzheimer, which may in fact be passed down on by either parent.

Sporadic Alzheimer’s risk factors and gene-environment interaction

Sporadic Alzheimer disease represents 95% of all cases and is caused by complex interactions between several genes and environmental influences. In contrast to the familial variant, sporadic Alzheimer disease is not inherited in typical patterns.

In infrequent instances, some gene variants can make one more susceptible to the disease without necessarily causing the disease. The risk gene that has been the most researched is the APOE-e4, although many individuals living with this variant do not develop Alzheimer at all, and other individuals without the gene do. This makes interactions between the environment and genes very important.

Environmental and lifestyle determinants that work with genetic predispositions are:

•             The level of education and intellectual involvement.

•             Cardiovascular health

•             History of head trauma

•             Sleep patterns

•             Chronic inflammation

•             Diet and exercise habits

These determinants may or may not have more or less genetic risks and this is what makes two individuals of the same genetic pattern different.

Familial Alzheimer’s Risk Factors and Mendelian inheritance

The rare type of the disease is Familial Alzheimer Disease (FAD), which makes up less than 5 percent of the overall cases. It is inherited in Mendelian modes, i.e. autosomal dominant inheritance as named after the extensive research of Gregor Mendel in the field of genetics.

In autosomal dominant inheritance:

•             It takes just a single copy of the mutated gene to be able to induce disease.

•             All children of an affected parent have a 50 percent probability of inheriting mutation.

As a rule, the disease is multigenerational.

•             There is equal opportunity among men and women.

There are three major genes, which cause familial Alzheimer:

– APP 1 protein- a protein that is synthesized by neurons and processed to produce amyloid.

•             Presenilin-1 (PSEN1)

•             Presenilin-2 (PSEN2)

The presence of mutations in these genes practically ensures that you develop Alzheimer, usually prior to the age of 65. To people whose one of their parents has one of these mutations, the question is what are the chances of developing Alzheimer as one of your parents had this disease? has a clearer answer—50%.

Compared to sporadic Alzheimer disease, in which it is difficult to predict, genetic testing of familial Alzheimer disease could give conclusive results on whether one possesses a deterministic mutation. Moreover, whereas sporadic Alzheimer risk assessment provides probability computations depending on a variety of variables, familial Alzheimer inheriting mathematics follow simpler lines.

Genes That Directly Cause Alzheimer’s (Deterministic Genes)

Some genetic mutations are almost a sure path to developing Alzheimer disease, usually at a younger age than sporadic cases. These weak yet strong genetic factors are the deterministic genes that give very important information on the disease process and answer the most important questions on the inheriting patterns when a parent has the Alzheimer disease.

APP gene and amyloid plaque formation

The central role of familial Alzheimer disease is played by the Amyloid Precursor Protein (APP) gene on chromosome 21. This gene has the instructions on how to make the amyloid precursor protein that exists all over the body specifically in large quantities in the brain cells. In the normal conditions, the cutting process of this protein is carried out by enzymes with precision.

This is an incorrect cutting process that occurs when the APP gene is mutated. As a result, the protein is cleaved at the wrong sites to form unusual fragments known as beta-amyloid peptides. These fragments have a threatening habit of clumping up to form the typical amyloid plaques that interfere with neuron-to-neuron communication and ultimately cause their death.

More than 50 mutations in the APP gene have been found to be related to early-onset Alzheimer. Most interestingly, the mutations are clustered on regions where enzymes typically cleave the protein. These altered patterns of cutting directly cause increased production of the sticky beta-amyloid-42 fragment, which speeds up the formation of plaques in the brain.

To those worried about heredity, this gene is one of the final answers to the question of whether Alzheimer is hereditary. The genetic pattern of the disease in the families carrying APP mutations is evident and thus, unavoidable in genetic counseling discourse.

PSEN1 and PSEN2: Presenilin mutations

The genes that encode proteins that form important components of gamma-secretase, an enzyme complex that cleaves amyloid precursor protein are called Presenilin-1 (PSEN1) and Presenilin-2 (PSEN2). These proteins virtually act as the scissors in the APP processing path.

PSEN1 on chromosome 14 represents most cases of early-onset familial Alzheimer. More than 300 mutations in this gene have been identified, so it is the most frequent inherited cause of early-onset Alzheimer. In PSEN1 mutations, onset of the disease is between the ages of 30 and 50 years old with some cases developing as early as in the mid 20s.

A somewhat less common inherited Alzheimer is caused by PSEN2, which is located on chromosome 1. PSEN2 mutations have a slightly later onset age, between 40 and 70 years old, on average. It has been found that about 40 mutations of this gene have been discovered.

These two presenilin mutations disrupt normal APP processing and thus result in the production of more detrimental beta-amyloid-42 fragments. The uniform action on all three deterministic genes highlights the key role of amyloid in the pathology of Alzheimer.

Autosomal dominant inheritance and 50% risk to children

In families with mutations in the APP, PSEN1 and PSEN2, the inheritance of Alzheimer disease is autosomal dominant. This pattern means:

1.            The mutated gene is required to be only one in order to cause the disease.

2.            The mutation is equal between males and females.

3.            The mutation is not parent-selective.

4.            Every child of an infected parent has a 50 percent probability of inheriting the mutation.

This type of inheritance gives a mathematical answer to the question: what are the chances of getting Alzheimer’s when a parent has it? In the case of these particular genes, the threat is exactly half – like a coin toss.

These mutations result in early morbidity and an incurable outcome that leaves an enormous burden on the family of a person harboring such mutations. These mutations can be detected by genetic testing prior to the onset of symptoms, but having such information comes with serious emotional and practical consequences. Others undertake testing because they want to make wise decisions regarding family planning, education and career development, and long-term care.

It is important to note that these deterministic genes only constitute approximately 1 percent of all cases of Alzheimer, with a preponderance in those who develop the disease earlier in life, prior to age 65. Most cases of Alzheimer involve more complex interplay between genes and the environment, as we have seen in other parts of this paper.

Risk Genes That Increase Susceptibility

On top of the deterministic genes that ensure the development of Alzheimer disease, many risk genes predispose but not predetermine the disease development. Such genes will help to resolve the heritability puzzle when the parent is affected by Alzheimer without deterministic mutations.

APOE-e4 and its population-specific impact

The apolipoprotein E (APOE) gene is the most powerful genetic risk factor of late-onset Alzheimer. APOE-e4 has a frequency of about 25% in the US population (allele frequency = 14). Individuals with two copies of the APOE-e4 (homozygates) are approximately 60 percent likely to have developed Alzheimer disease by the age of 85. In addition, homozygotes constitute only 2 percent of the total population, but with respect to Alzheimer, they are estimated to constitute 15 percent of the cases.

The interesting detail about APOE-e4 is that its effect is not constant in all populations. In people of European origin, it is a serious risk factor, but research demonstrates that it has no connection with neurodegeneration in American Indian populations. Such variation suggests that interrelationships between genetics and other variables are not straightforward.

In individuals with APOE-e4, the symptoms are likely to occur 7-10 years before those who do not possess the aforementioned gene. Virtually every APOE-e4 homozygote develops brain pathology after the age of 55 years, and only approximately half of those without APOE-e4.

Other risk genes: CLU, CR1, PICALM, ABCA7

Alzheimer has been associated with several other risk-related genes with smaller impacts than APOE-e4:

•             CLU (Clusterin): assists the brain in clearing toxic beta-amyloid proteins. This T allele of rs11136000 in CLU correlates with lower risk of developing Alzheimer.

CR1: generates immune-safe proteins. There may be some inflammation involved in the development of Alzheimer.

•             PICALM: It is involved in the intercellular communication of neurons as well as in beta-amyloid processing. C allele of the rs541458 is protective.

ABCA7: Cholesterol. This T/G heterozygote is risky.

Interestingly, the associations of variants in CR1 and CLU genes with Alzheimer are altered by APOE-e4 status. Of APOE-e4 transporters, the variants have minimal influence on the risk of disease.

Genome-wide association studies (GWAS) findings

Recent genome-wide association studies have unleashed a host of new insights into the genetics of Alzheimer. A meta-analysis found 75 risk loci of which 42 were novel. This was later confirmed by another study which found another 15 loci.

It is estimated that the genetic heritability of Alzheimer is 60-80, which also contributes to the importance of genetics even in sporadic cases. Although these findings have been made, much of this heritability is still unclear.

Most recently discovered genes are grouped into three biological pathways: cholesterol metabolism, endocytosis/phagocytosis, and immune system activity. This shows that these systems play a role in the development of diseases.

Genetic Testing: Who Should Get It and Why

Whether or not one should go through genetic testing to identify Alzheimer is a question that should be considered especially when the person has the disease or when a parent has the disease. The benefit of genetic testing is that some understanding of the risk factors is acquired but there are a number of significant limitations and considerations.

Genetic test for Alzheimer’s: clinical vs at-home

Clinical genetic testing by health care providers is very different to direct-to-consumer (DTC) over-the-counter tests. In clinical testing, this usually includes extensive counseling and medical care and in at-home testing this usually is not the case. Genetic testing is not a routine recommendation of most healthcare professionals who treat late-onset Alzheimer’s disease as it has many causes, and the causes are not often due to single genes.

In some cases clinical testing can be suitable to early-onset Alzheimer:

•             Patients whose families have a history of autosomal dominant dementia and those who developed it early on.

•             Individuals who have a first-degree relative who harbors a known mutation in PSEN1, PSEN2 or APP genes.

•             Symptomatic persons with suspected onset of AD at an early age and unclear family history.

Direct-to-consumer tests, such as 23andMe, can determine the variants of APOE but do not give much information on how to interpret the results. In this regard, specialists suggest that any at-home test results should be discussed with a genetic counselor.

Limitations of APOE testing for late-onset Alzheimer’s

APOE testing is not a sure way of predicting who gets Alzheimer. Approximately 42 percent of persons with Alzheimer disease do not carry the APOE-e4 variant and majority of individuals carrying the APOE-e4 variant never develop the disease. Thus, clinical genetics teams do not usually provide the APOE testing as it does not change medical recommendations greatly.

Due to his research, now, no professional organization recommends regular testing of the APOE gene. Actually, the medical care is not affected by the test results as there are no preventive medicine given with certainty that it will slow down the onset of Alzheimer.

Ethical and emotional considerations of testing

The outcomes of genetic tests can be devastating to people and families. The employment and access to disability, long-term and life insurance may be influenced by the test results. In this respect, individuals who are to test must buy insurance coverage first.

Testing has different psychological effects on different people. A 5-7 percent threat of getting Alzheimer may devastate one individual and soothe another who has an 93-95 percent chance of never getting this disease. Other studies have reported that disclosure does not result in high levels of anxiety, but does raise levels of test-related distress.

Above all, genetic pre- and post-testing counseling is necessary. A counselor may assist in deciding the complicated issue, as well as analyzing the results within the framework of the general health.

What to Do If You’re at Higher Risk

It may seem daunting to learn about your genetic risk of getting Alzheimer, but there are tangible things you can do without regard to whether or not you are genetically predisposed. Even in people with a genetic inclination to such conditions, lifestyle factors play a large role in the health of the brain.

Brain-healthy lifestyle recommendations

• Brain-healthy behaviors can lower your risk or slow symptom development even in the case of a family history of Alzheimer disease:
• •      Get to the heart of the matter: What is good to your heart is good to your brain. Even moderate exercise such as walking is sufficient to help lower the risk of Alzheimer significantly.
• •      Adhere to brain-protective diets: both the Mediterranean and MIND diets focus on foods that are helpful in maintaining the health of the brain, such as leafy greens, berries, whole grains, fish, and olive oil.
• •      Challenge the brain: Challenge your mind with skills, literature, puzzles or imagination.
• •      Social ties: Good social networks are associated with healthy thinking in later life.
• •      Stress management: Chronic stress is a contributor to inflammation and can contribute to worsening cognitive impairment.

Monitoring cognitive health over time

Guard your cognitive health, particularly when you are at greater genetic risk:

•             See your doctor regularly to establish a cognitive functioning norm.

Examples of initial warning signs to consider: There is sustained impaired memory in day to day functioning.

Neuropsychological testing: This is where the little alterations in thinking are taken into consideration.

Participating in research and clinical trials

• The personal gains of allied contributions to research on Alzheimer relate to the overall development of science:
• •      Participate in research targeted at people with family history.
• •      Find out about the observational studies that monitored cognitive changes with time passing.
• •      Consider prevention trials of interventions prior to the emergence of symptoms.
• •      Go to sites like ClinicalTrials.gov to search what is going on in your community.

Conclusion

Awareness of the genetic nature of Alzheimer is a bright and obvious thing to everyone who has a parent with this disease. Natural history of the family is definitely a predisposing factor, but it does not doom anybody. It is complex genetic mechanism, and therefore genetic basis of familial Alzheimer can be considered the augmentation of the pattern, while genetic basis of sporadic cases is the strenuous unity of the genes and the environment.

One of the reasons that some families show early-onset cases with 50% inheritance rates and others are mixed despite the similar genetic background of the two is this difference between deterministic genes (APP, PSEN1, PSEN2) and risk genes (such as APOE-e4). This fact helps families to make a good decision regarding using genetic and preventive tests.

Genetic testing on the other hand comes with some advantages as well as disadvantages. Tests can also detect particular mutations, but not predict with certainty who will be affected by late-onset Alzheimer. In this regard, the majority of healthcare providers would not prescribe testing regularly unless they are at risk of certain factors. There are also important emotional and practical implications of test results that should be given due consideration.

Probably best of all, studies indicate that we do not have nothing to do with genetic predisposition. Lifestyle choices that are brain healthy could substantially decrease the risk or postpone the development of symptoms. Cognitive resilience is promoted by regular exercise, healthy eating, brain involvement, interaction with others and management of stress.

The path between the acquisition of scientific knowledge about the risk of Alzheimer and the active implementation of preventive strategies is characterized by a rational balance of scientific and individual welfare. Genetic factors have a significant influence but they are only a small part of a huge puzzle. We have the opportunity to face the challenge of inherited problems with training and optimism, with lifetime participation in research and preventive health. Certainly, at the end of the day, knowledge of risk factors can be used not to evoke fear but to motivate informed action toward better brain health across life.

Key Points

Knowing your risk of developing the form of dementia known as Alzheimer when a parent has it is a complicated genetic issue, but knowing is power, and you can take certain steps to keep your brain healthy.

• Your risk of developing Alzheimer because of having a parent with the disease is increased, but only rare cases in the family (less than 5% of all cases) assure you of passing the disease to your children with 50% certainty.

• APOE-e4 gene type: 25 percent of people have this gene type and are at a much higher risk of developing late-onset Alzheimer, although it does not necessarily lead to the disease.

Genetic testing is largely limited in the prediction of late-onset Alzheimer and is not regularly suggested by the medical community because of its unclear medical value.

Brain-healthy lifestyle habits, such as cardiovascular activities, Mediterranean diet, cognitive stimulation and social life, could help decrease the risk independent of genetic susceptibility.

In the case of the former, participation in research work and monitoring of cognitive well-being with the help of regular examinations represent a personal benefit, and the second becomes a part of the scientific knowledge base.

Although genetics are a significant factor in the development of Alzheimer, it is only one of the many factors. The promising fact is that lifestyle determinants can play a significant role even among people who are genetically predisposed. Instead of being afraid, you should be motivated by being aware of your risk factors to take informed action to ensure you are enjoying optimal brain health as long as you live.

FAQs

Q1. Does this mean that I will surely have Alzheimer risk just because my parent does?

No, having an Alzheimer parent makes you more likely to get it but does not mean that you will. There are only a few rare family cases (less than 5%), which have 50% probability of inheritance. The majority of cases are sporadic and are associated with complicated interactions between genes and the environment.

Q2. What is the APOE-e4 gene and its impact on risk of getting Alzheimer?

The gene variant that causes a high risk of late-onset Alzheimer is called APOE-e4. It occurs in nearly a quarter of the population. It is the most powerful, well-known genetic risk, but having APOE-E4 does not mean that you will develop Alzheimer, and most people who do not have it still acquire the disease.

Q3. Is it a good idea to undergo genetic testing of Alzheimer?

Healthcare professionals do not encourage the routine use of genetic testing to diagnose Alzheimer’s, particularly when the disease occurs later in life. It is restricted in its ability to determine who will become infected with the disease, as well as in that it does not change medical care. With respect to testing, it is natural to communicate to genetic counselor that you know what the results are.

Q4. How can I change my lifestyle to decrease my risk of Alzheimer?

Brain-healthy habits can help lower your risk or slow the development of symptoms. These include regular body exercises, consuming of a Mediterranean or MIND diet, having a busy mind, close people in your life, and dealing with stress. Such lifestyle influences can be very impressive even among people with a genetic predisposition.

Q5. So how do I keep track of my cognitive health when I have a higher risk of Alzheimer?

You need to visit your health practitioner to check on your mental health periodically so that you can develop a benchmark of your mental capacity. Consider the implications of red flags such as having on-going trouble with memory that disrupts normal living. Consider neuropsychological testing, too, when you fear that your thinking is subtly different. Also, it can be personally rewarding to take part in research studies to benefit both the science and the individual.

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