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Alzheimer's disease is a complex disorder with multiple causes. One important factor in the development of Alzheimer's disease is genetics. In this article, we will explore the role of genetics in Alzheimer's disease. In particular, we will discuss how the ApoE gene can increase or decrease a person's risk for Alzheimer's disease.
Alzheimer's disease (AD) is the most common cause of dementia in the elderly.
People with Alzheimer's exhibit a progressive decline in memory, function, language, and other areas of cognition.
This condition is characterized by the formation of amyloid plaques and tau tangles in the brain, which we will explore in detail in the later sections.
While many genes have been studied in association with Alzheimer's, the only strongly confirmed genetic risk factor across many studies for early, and late-onset AD is apolipoprotein E (ApoE) genotype, with the E4 allele being an AD risk factor and the E2 allele being protective.
The ApoE gene is responsible for producing a protein called Apolipoprotein E.
The APOE protein combines with fats (lipids) and cholesterol in the body to form lipoproteins.
It is responsible for metabolizing and clearing out fats and cholesterol from the body.
Besides its role in fat metabolism, it’s also been found to regulate the immune system and cognitive (thought) processes within the brain.
Most of the ApoE is produced in the liver.
The rest of it is produced in the brain.
We all have the ApoE gene but carry different versions of it, just as we have different blood types.
The three versions of the ApoE gene are E2, E3, and E4.
They are also called the isoforms of the ApoE gene.
Each of these results in small differences in the ApoE protein.
These differences alter the activity of the protein and the lipoproteins it is associated with.
The ApoE3 type is believed to be the most common version present in humans.
Since we carry two copies of every gene, one each from the mother and father, there are six possible combinations:
The E3/E3 is the most common type found in about 60% of the general population.
E4/E4 has the strongest genetic link for Alzheimer’s and is associated with a higher than normal risk.
E2/E4 and E3/E4 also increase the risk of Alzheimer’s, though not as much as E4/E4.
There are two types of Alzheimer's, early-onset and late-onset.
Both have a genetic association.
This is the more common type of the two.
The symptoms start to appear roughly in the mid-60s.
There's no direct genetic cause for late-onset Alzheimer's.
However, certain isoforms of the ApoE gene are associated with the risk of Alzheimer's.
We'll see more about this in the upcoming section.
This is a rare type of Alzheimer’s.
In fact, it represents less than 10% of all Alzheimer’s cases.
The symptoms can start to appear anywhere between the mid-30s to the mid-60s.
Three genes have been implicated in the risk of Early-onset Alzheimer’s. They are
The genetic association centers around the build-up of amyloid plaques, a hallmark of Alzheimer’s disease.
Many molecular and cellular changes occur in the brains of people with Alzheimer’s.
Two protein clusters are involved in the development of Alzheimer’s.
Amyloid plaques are aggregates of a protein called beta-amyloid.
This protein is a part of a larger protein called amyloid precursor protein, or APP in short.
Beta-amyloid is made up of 42 amino acids (beta-amyloid 42) and has a sticky nature.
So they easily bind to one another to form amyloid plaques.
Some genetic variants that change the function of gamma-secretase are associated with early-stage Alzheimer’s disease.
Gamma secretase is involved in the cleaving of APP to form beta-amyloid 42.
The mechanism of how beta-amyloid 42 build-up becomes toxic to the brain is unclear.
According to some studies, the plaques release free radicals (unstable molecules that damage cells) that end up attacking the neurons.
Research also suggests that the plaques result in an imbalance in calcium levels, ultimately leading to neuronal death.
ApoE and Amyloid Plaques
ApoE has been associated with plaque formation.
It has multiple functions in regulating beta-amyloid clearance, aggregation, and deposition, all of which can affect Alzheimer’s pathogenesis.
Research shows that ApoE competes with the amyloid proteins for binding with the receptors.
ApoE4 exacerbates the brain accumulation and subsequent deposition of beta-amyloid proteins.
Neurons are cells that are the fundamental units of the brain.
Healthy neurons are supported by structures called microtubules.
Tau proteins are molecules that bind and add stability to the microtubules.
With Alzheimer’s, the tau proteins start to detach from the microtubules and instead bind to one another, forming plaques (known as tau tangles).
The tangles block the communication pathway between neurons, causing their dysfunction.
Some studies have suggested that tau protein accumulation often occurs in the regions of the brain associated with memory.
ApoE and Tau Proteins
The research on how different isoforms of ApoE contribute to tau plaque formation is a bit hazy.
Some studies suggest that ApoE contributes to beta-amyloid Alzheimer’s pathology but not tau Alzheimer’s pathology.
However, a 2019 study that explored the relationship between ApoE4 and Tau in Alzheimer’s found that ApoE4 carriers did have more tau tangles in the brain than noncarriers.
This suggests that ApoE4 may accelerate tau pathology in the key Alzheimer’s Disease region.
Yet another study found a relationship between the ApoE2 isoform and increased tau pathology.
The mice injected with the ApoE2 isoform exhibited a significant increase in tau aggregates and behavioral abnormalities.
The E4 allele frequency is estimated to be about 15% in the general population but is around 40% in Alzheimer’s patients.
ApoE4 is thus considered a risk factor for Alzheimer’s.
However, it is important to note that not all people with E4 will develop Alzheimer’s.
At the same time, not carrying E4 doesn’t mean one will not develop Alzheimer’s.
Other brain-related changes that occur as you age also may be causative factors of Alzheimer’s.
Some of them include:
The idea of using ApoE4 as a target for Alzheimer’s treatment revolves around delaying the onset and progression of dementia instead of curing the condition itself.
Such treatment would likely slow down the neurodegenerative decline in ApoE4 carriers.
A study claims that such ApoE4 targeted treatments in ApoE4 carriers without dementia could slow down the onset of the condition by 7 years!
Treatments that target ApoE4 also help prevent the development of associated conditions like coronary heart disease and atherosclerosis.
Some therapeutic approaches are:
Gene editing is a genetic engineering technique where a gene is changed to manipulate its function or silence it.
ApoE3 and ApoE4 vary only at one position.
Using a technology called CRISPR (a popular technique used for DNA modification), ApoE4 editing has been carried out.
Immunotherapy involves activating our immune system by raising antibodies against the unwanted ‘guest.’
Anti-ApoE immunotherapy can help prevent the accumulation of amyloid plaques.
A novel therapeutic approach uses small molecules called structural correctors.
These molecules correct misfolded protein variants and convert them into their wild-type (normal) form.
ApoE4 protein structure has two domains - the N domain and the C domain.
Interaction between these two domains has been implicated in the pathogenesis of Alzheimer’s. Two ApoE4 correctors disrupt the interaction between the domains.
This transforms ApoE4 into an ApoE3-like molecule.
A mimetic is a molecule that can biologically mimic other molecules like hormones, enzyme substrates, viruses, and other molecules.
These apoE mimetics have both anti-inflammatory and neuroprotective actions.
Treatment with apoE mimetics was shown to significantly improve behavior and reduce inflammation and pathology of the disease in transgenic mice.
The ApoE gene encodes the apolipoprotein, which forms lipoproteins mainly involved in cholesterol and fat metabolism in the body.
There are three types of ApoE gene, namely ApoE2, ApoE3, and ApoE4. Each type gives rise to slightly structurally different proteins. E3 is the most common isoform found in people.
The ApoE4 isoform is associated with elevated levels of circulating cholesterol. This isoform has been implicated in many diseases, especially Alzheimer’s. 40% of people with Alzheimer’s are found to have the E4 allele.
Gambling addiction is a serious mental health disorder that can devastate a person’s life. It is characterized by an intense and persistent urge to gamble, despite the negative consequences. Some people seem to be more prone to gambling addiction than others, and scientists are beginning to wonder if there is a genetic component to this addiction. If you have a family member struggling with gambling addiction, you may be at greater risk of developing the condition. If you think you may be addicted to gambling, it is important to seek professional help.
Behavioral addictions revolve around the brain’s reward system, predominantly driven by the dopamine hormone.
Dopamine, the feel-good hormone, plays a critical role in many types of addiction, including gambling, owing to its pleasure-inducing effects.
Feel-good activities like sex, shopping, drug usage, smoking, gaming, and gambling can trigger dopamine release.
The effects of dopamine make the person repeat the activity, and when this continues for a while, it becomes an addiction.
Dopamine’s reinforcement effect seems to play a bigger role in addiction than the direct effect. What does this mean?
Dopamine signaling during pleasurable activities causes some changes in how the brain cell functions.
It hampers certain pathways that enable the person to keep repeating the activity easily without giving it much thought.
This repetitiveness leads to addiction.
Studies suggest that people addicted to the thrill of gambling, in fact, have a lower activation of the reward pathways in the brain.
This is described by a term called the reward deficiency model.
This model suggests that people prone to addiction have a dormant reward system, making them more prone to reward-stimulating activities like gambling.
Most of us can manage to wager a few bets without running into too many problems.
But a few people encounter gambling addiction, which can significantly affect their lives.
This begs the question: are certain people naturally more tuned to develop gambling addiction due to their genetic makeup?
A study published in the June 2017 issue of the Archives of General Psychiatry has attempted to answer this question.
The study was conducted by scientists from the University of Missouri-Columbia and Australia's Queensland Institute of Medical Research.
It involved about 2,700 women and 2,000 men from the Australian Twin Registry.
The researchers asked a bunch of questions to this group and compared the responses between identical twins (with the same genetic makeup) and fraternal twins (50% similar genetic makeup).
The findings show that if a twin had a gambling problem, an identical twin had an increased risk for gambling than a fraternal twin.
The study further reported that while almost all study members gambled, men (3%) were more likely to be gambling addicts than women (1%).
The author says that “genes rule at least 50 percent of a person's propensity to gamble irrespective of sex.”
Exploring the science behind increased propensity to gamble
An analysis of the molecular genetics of gambling addiction revealed specific forms of genes (called alleles) that link to brain chemicals (called neurotransmitters) playing a role in pathological gambling.
This link suggests that certain people may be more prone to gambling addiction due to certain genes influencing how their brains interact with the happy hormones.
People with these genetic changes associated with gambling addiction can pass them down to their children, resulting in a hereditary component of gambling.
The same study identified genes that play a role in the transport of dopamine and serotonin, which were common in people with gambling addiction.
The Monoamine-Oxidase A or the MAO-A gene, in particular, showed a significant link to gambling addiction.
The MAO-A gene is a key contributor to serotonin and dopamine distribution
Certain changes in this gene make people more dependent on pleasurable feelings due to dopamine elicited by gambling events.
For example, a study found that some men carry a change in the serotonin gene, resulting in increased serotonin production when gambling.
This increased production may make gambling more addictive to those with this genetic change.
This change was not identified in females, explaining why men may be more prone to gambling addiction.
Compulsive gambling is found in higher numbers among those younger than 65.
The risk-taking behavior tends to decline as people get older.
Those with mental health disorders like depression, anxiety, bipolar disorder, and attention deficit hyperactivity disorder (ADHD) are at a greater risk of developing a gambling problem.
Stress is frequently identified as a trigger of gambling behavior.
According to a study, almost 50% of individuals with gambling disorders undergoing cognitive behavioral therapy identified negative emotional states, such as stress.
The people around you influence your behaviors and choices.
Surrounding yourself with people who constantly gamble can increase your tendency to gamble due to peer pressure.
Living in an environment where gambling is widely accepted and regularly practiced can significantly increase the chances of becoming a compulsive gambler.
Post-traumatic stress disorder (PTSD) and gambling disorder can go hand in hand.
Studies show up to 34% of people with gambling problems also have PTSD.
In conclusion, gambling addiction may have a genetic component. However, it is also influenced by environmental factors.
If you think you may have a gambling problem, talk to your doctor or mental health professional.
They can help determine if you have a gambling problem and provide insights into the available treatment options.
Our body is made up of cells.
All cells comprise smaller components called cell organelles, each with a specific function that it performs within the cell.
One such organelle is the mitochondria, responsible for converting energy from food into a form the cell can use.
Since the mitochondria produce energy, it is also called the powerhouse of the cell.
Each cell contains hundreds of mitochondria floating in a fluid in the cell called the cytoplasm.
While most of the DNA in a cell is packed into a structure called the nucleus, a small amount of DNA is also found to occur in the mitochondria.
This genetic material is called mitochondrial DNA or mtDNA.
Almost all the cells in our body contain hundreds of copies of mitochondrial DNA, unlike 23 pairs of chromosomes in autosomal, Y- and X-DNA (the DNA you receive from your parents).
The mitochondrial DNA contains 37 genes, all of which are required for normal mitochondrial function.
13 of these genes give instructions for making enzymes involved in oxidative phosphorylation.
Oxidative phosphorylation is a process that uses oxygen and simple sugars to create ATP (the main source of energy for the cell).
The remaining genes in the mitochondrial DNA provide instructions for producing molecules responsible for protein synthesis and other functions.
We inherit our mitochondrial DNA from our mother. For this reason, we share our mtDNA with our mothers, sisters, brothers, maternal grandmothers, aunts, uncles, and other maternal relatives.
Since mitochondrial DNA undergoes a high frequency of abnormal changes (called mutations), the mtDNA sequences between closely related maternal relatives may differ.
Mitochondrial DNA is complex; therefore, it may be difficult to predict how mtDNA mutations pass from the mother to her child.
These are chronic (long-term) genetic disorders that occur when the mitochondria cannot produce enough energy for the cell to function.
These disorders are usually inherited from the mother.
Mitochondrial disorders can affect any part of the body. A few common mitochondrial disorders are:
Mitochondrial disorders are fairly common; around one in 5,000 people are diagnosed with a condition yearly.
Mitochondrial inheritance
Mutations in the mtDNA that cause mitochondrial disease are inherited exclusively from the mothers, and there is a 100% chance that every child in the family will inherit the condition.
This test helps people trace their matrilineal or mother’s line of ancestry through their mitochondria.
Since everyone has mitochondria and each individual inherits them from their mother, people of all genders can take an mtDNA Test.
Mitochondrial DNA testing uncovers an individual’s mtDNA haplogroup (the ancient group of people from whom their matrilineage descends. Apart from this, mtDNA testing also helps determine a common maternal ancestor or look for diseases inherited from this line.
Once a blood sample is collected for the mtDNA testing, it is transported safely and securely to the laboratory.
In many cases, the sample collection may happen in the lab.
Once the sample has been prepared and the circular mtDNA isolated, it is divided into three sections:
Several genetic laboratories and companies perform mtDNA testing.
You can look for the one closest to you.
Always check for the necessary accreditations and certifications of the laboratory before going through with the test.
Anyone can take an mtDNA test for the following reasons:
The cost for mitochondrial DNA testing varies at different laboratories based on their machines, technology, and experience.
The cost of the test can also vary depending upon whether you choose to use a self-test kit or a laboratory-based one.
While regular DNA gives plenty of information about our ancestry and lineage and helps establish paternity, mitochondrial DNA offers several benefits as well:
The primary challenge in mtDNA analysis is that mtDNA shows heteroplasmy or the possibility of mutations.
This gives rise to two different mtDNA sequences.
So, at the time of analysis, there should be at least two differences between the sample and reference material.
Autosomal DNA testing is a powerful tool that can be used to learn about your family history. This test looks at your DNA, the unique genetic code that makes up your identity. By looking at your DNA, experts can tell you what countries your ancestors came from and how they are related to you. Autosomal DNA testing can also be used to find out if you have any genetic diseases or conditions. Autosomal DNA tests are relatively new and are becoming more popular as they become more affordable. If you're considering getting an autosomal DNA test, here's what you need to know.
Almost all humans (with some exceptions) are born with 23 pairs of chromosomes.
The X and the Y chromosomes, also called the sex chromosomes are a part of the 23rd pair.
The other 22 pairs are called the autosomal chromosomes or the autosomes.
Autosomes are numbered roughly according to their sizes.
Chromosome 1 has approximately 2,800 genes, while chromosome 22 has approximately 750 genes.
Autosomal DNA is the DNA inherited from the autosomal chromosomes.
These genes in the autosomal DNA are 99.9 percent identical in every human being.
But small changes in these genes determine the rest of your genetic makeup, whether you inherit certain traits and your risk for several health conditions.
Genetic material is passed on from parents to children, and so are certain genetic conditions.
However, not all health conditions have the same inheritance pattern.
Autosomal dominant and autosomal recessive inheritances are two ways a genetic condition could pass on from one generation to the next.
Autosomal dominant inheritance
In autosomal dominant inheritance, one copy of the altered gene is sufficient for the trait/condition to express itself.
Only one parent needs to pass the altered gene.
Every child of this parent will have a 50% chance of inheriting the altered gene and thus the genetic condition.
Only changes that occur in the DNA of the sperm or egg can be passed on to children from their parents.
Autosomal recessive inheritance
Conditions inherited in an autosomal recessive pattern need two copies of the altered gene for expression.
To pass it on to their children, both parents must carry at least one copy of the altered gene.
They may not express the conditions themselves if they carry a single altered copy of the gene.
In other words, they are “carriers” of a particular genetic condition.
If two carriers of the same condition have children, each child has a 25% chance of being affected by the condition, a 50% chance of being a carrier of the condition, and a 25% chance of receiving 2 normal copies of the gene.
Autosomal DNA tests look at the autosomes, the 22 pairs of chromosomes that mostly everyone has.
Typically, experts use a DNA array to examine several thousand genetic regions or markers across all the 22 pairs.
Once this information is collected, they match it in their database with similar information from others.
The larger the area of the genetic region you share with another person, the more closely you are related.
Autosomal DNA tests provide greater genetic information than Y-DNA and mitochondrial DNA (mtDNA) tests, which cannot reveal much information about close relatives or recent ancestry.
As mentioned above, scientists look at shared regions of DNA between you and several other people in the database to determine how closely you are related to someone.
The more shared markers you have with someone, the closer you are related to that person.
Scientists compare your DNA to DNA from people deep-rooted in several parts of the world to determine ethnicity.
If your DNA resembles that of people from Italy, that part of your DNA is said to have an Italian lineage.
This is how it is possible to learn where your ancestors lived centuries ago.
An autosomal DNA test is ideal for someone in the following scenarios:
Everyone can take an autosomal DNA test regardless of age and gender.
Autosomal DNA tests are popular options for identifying your close and distant relatives.
In fact, this test can reveal almost all your second and most of your third cousins.
It is pretty accurate to confirm parent/child relationships.
Distant relatives may be harder to find, but some tests can reveal even up to the eighth and tenth cousin!
Depending on the service provider you choose, the process may be slightly different.
However, there are some common steps in taking an autosomal DNA test.
Each service will use a different algorithm and have different reference genomes to define particular ethnicities and geographic regions.
So, the same person can get different ethnicity providers from different companies.
In fact, siblings can get dramatically different results from the same company.
In conclusion, autosomal DNA testing can be useful for those looking to learn more about their ancestry. It can also be used to help identify relatives, both close and distant. With the advent of online databases, such as 23andMe and AncestryDNA, DNA testing has become more accessible and affordable than ever. However, it is important to remember that the results of this type of test are not always accurate and should be interpreted with caution. If you are considering taking an autosomal DNA test, you should speak to a genetic counselor or other healthcare professional first.
It's no secret that some people are just better at napping than others. But have you ever wondered if there's a scientific reason for why some people can fall asleep anywhere, anytime? Turns out, there might be. A new study suggests that a excessive daytime sleepiness may be linked to your genes.
Researchers have identified a number of genes associated with excessive daytime sleepiness (EDS).
In the sample report below, we've attempted to analyze some important genes that increase the risk for EDS.
You can identify your genetic risk of EDS by using your 23andMe DNA data and placing an order for the Gene Sleep Report.
EDS (also known as hypersomnia) refers to the inability to stay awake and alert during normal waking hours, resulting in unexpected sleep or drowsiness lapses.
It can even occur after long stretches of sleep.
There are two types of hypersomnia; primary and secondary.
Some symptoms of hypersomnia include:
A 2019 study in Nature Communications documented that nearly 10–20% of people deal with excessive sleepiness to some degree.
Studies have shown that certain genetic variants influence daytime sleepiness, which explains why some individuals need more sleep than others.
Twin study results have estimated a 38% genetic variance in daytime sleepiness.
Studies have found an association between EDS and changes in certain genes like HCRTR2, PATJ, AR-OPHN1, KSR2, and PDE4D.
The HCRTR2 gene encodes a protein belonging to the G-protein coupled receptor, involved in regulating appetite, energy balance, neuroendocrine functions, and wake promotion.
Latest research studies suggest that variations in the HCRTR2 gene may influence the sleep-wake process.
The most common causes of excessive sleepiness include:
Research has also indicated that other health conditions can increase the risk of excessive sleepiness. Some of them include:
Studies have shown that EDS is associated with an increased risk of developing coronary heart disease and stroke.
However, the risk can be managed by improving the quality of sleep.
People with EDS also have poorer health than comparable adults.
According to a study, EDS is associated with negative effects on cognitive function.
In fact, EDS is a common symptom in neurological conditions like Parkinson’s and psychiatric conditions like depression.
Sleep disorders like insomnia, narcolepsy, and restless leg syndrome and other conditions like depression and obesity can cause EDS.
Identifying and treating these conditions can help shorten daytime naps.
Ensuring a dark and cool sleep environment, getting adequate physical activity during the daytime, reducing alcohol consumption and smoking, and adopting a calming bedtime routine can improve overall sleep hygiene and reduce the effects of sleep-related disorders.
Several medications are used to treat sleep disorders, but doctors most commonly prescribe this along with another treatment.
Commonly prescribed medications for EDS are modafinil, sodium oxybate, melatonin, and methylphenidate.
https://pubmed.ncbi.nlm.nih.gov/31409809/
https://pubmed.ncbi.nlm.nih.gov/27992416/
https://pubmed.ncbi.nlm.nih.gov/29783161/
Polycystic ovarian syndrome (PCOS) is a common condition that affects hormones in women in their childbearing years.
Most women with PCOS produce excessive amounts of androgens (male sex hormones), a condition called hyperandrogenism.
In this condition, one or both ovaries produce multiple small, immature ovarian follicles that appear like cysts on medical imaging.
This happens because abnormal hormone levels prevent follicles from growing and maturing to release egg cells.
PCOS is one of the leading causes of female infertility and increases your risk for other conditions like diabetes and hypertension.
By 40 years, around 10% of overweight women with PCOS develop high blood sugar levels, and around 35% develop prediabetes (high blood sugar levels but not high enough to be called diabetes).
Though many women with PCOS do not show any signs or symptoms, a few common symptoms of this condition include:
Around 70% of women with PCOS show abnormal hair growth.
Image: Is PCOS Genetic? Symptoms of PCOS
PCOS is common and affects around 6 to 10% of women worldwide.
The exact cause of PCOS is unknown. However, sufficient research shows that the condition runs in families.
Evidence shows that genetics plays a role in the development of PCOS.
Few other causes that may contribute to the development of PCOS are:
High androgens released by the ovaries result in irregular menstrual cycles, excess hair growth, and acne. The excess androgen also contributes to immature ovarian follicles that form cysts.
Women with PCOS tend to have a higher amount of insulin in their blood.
Increased insulin causes the ovaries to produce greater amounts of androgens and increase insulin resistance.
Being overweight or obese increases the amount of insulin produced by the body, further increasing insulin resistance and resulting in diabetes.
Women with PCOS have chronic low-grade inflammation that can further aggravate the condition.
Since women who develop PCOS have a family member with the same condition, it is said that PCOS may have a genetic component.
In fact, around 20% to 40% of women with PCOS have an affected family member.
Currently, it is believed that PCOS occurs due to an interplay between genetic and environmental factors.
PCOS is a polygenic (caused by multiple genes) and multifactorial condition.
Several genes are said to be associated with PCOS, such as
A few other genes that may contribute to the development of PCOS include:
Factors that increase a woman’s likelihood of developing PCOS can be lifestyle or genetics-related. Common risk factors for PCOS include:
If you know your risk for PCOS, here are some effective ways to prevent it:
While there is no cure for PCOS, appropriate and timely measures can help manage symptoms.
Image: Is PCOS Genetic? PCOS management at home
