This document discusses genetics and dementia. It begins by outlining the aims to review links between dementia and genes, identify those at increased risk, and discuss implications for families. It then discusses how most dementia is not inherited, but some forms have genetic components. These include familial Alzheimer's disease and other inherited forms like Tay-Sachs disease. Environmental factors and genes also contribute to sporadic Alzheimer's disease. The document provides guidance on identifying inherited patterns through family histories and genetic testing to help families understand their risks.
11. Parents
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At conception
Autosomal dominant inheritance where one parent has the condition
12. Parents
Sperm or eggs
At conception
Autosomal dominant inheritance where one parent has the condition
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the condition
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Autosomal recessive inheritance where both parents are carriers
Carrier for the
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Carrier for the
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19. Parents
Sperm or eggs
At conception
Autosomal recessive inheritance where both parents are carriers
Carrier for the
condition
Carrier for the
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20. Parents
Sperm or eggs
At conception
Autosomal recessive inheritance where both parents are carriers
Carrier for the
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Carrier for the
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Carrier for the
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Carrier for the
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This is a presentation that was used at a Primary Care conference in 2012 during an Age Concern supported session. The remit was the current uncertainty about the role genes play in dementia, the needs of patients and what Age Concern would like people to know about risk factors.
The aims of this session are to review and understand the links between dementia and genes, to consider how a health professional might identify those at increased risk and then to to discuss the implications for the family.
Daniel Pollen, who was a Professor of Neurology and Physiology at the University of Massachusetts, identified in his book “Hannah’s Heirs” the compelling story of Hannah whose family have made a monumental contribution to understanding about Alzheimer’s disease, and how it may affect. It is a paper that is well worth reading and certainly what I think is one of the key things is the fact that what they identified with this particular family is that we get some parts of our DNA from various members of the family going back over generations and sometimes it is really important to identify whether those strands of DNA carry alterations that can cause problems or actually alterations which are just normal within a family unit.
Dementia affects around 800,000 people in the United Kingdom and worldwide there are over 4 million people who have been identified as having dementia. The causative factors include so many factors when looking at a chronic condition; age being the most likely factor; obviously genes which I will talk about some more but I think one of the things that the Alzheimer’s Society would say is that environmental factors, certainly things such as diet, obesity, smoking and life style choices and therefore a patients overall general health can have an even bigger impact on the chance of somebody getting dementia. The genetic causes of dementia are very rare and we still know so very little about them.
Most dementia is not inherited. Some things that we do know that definitely have an impact on dementia is the age of a person. You are all well aware as people get older so the chances of them getting dementia increases. We also know there are things such as acquired immuno-deficiency syndromes, such as AIDS for example, which does a give much higher risk of somebody getting dementia.
Also that there are other conditions, such as central nervous system infections, vascular disease, which are very commonly associated with dementia.
Brain tumours – although people would say well that’s not really dementia just an impact but the symptoms seen in a patient can be exactly the same.
Some patients can react in a toxic way to drugs, which can cause symptoms which are very similar to what you would see in a patient with dementia.
We also know that syphilis, a sexually transmitted disease, can cause a dementia like response in individuals, especially if the syphilis has not been picked up early and treated.
There are other metabolic nutritional deficiencies which can lead to symptoms which are very dementia related.
What I want to look at is how you might actually identify a family in which there is an inherited condition rather than a condition which is due to life style.
If you have a look at this drawing in which females are circles, males are squares, this is a three generational family history and it is often easier to draw it out into what is called the pedigree, as you can see here, than to write out in notes.
If you look at this particular family you can see a condition in which somebody has been diagnosed at 52 and they have then given a family history in which their mother, uncle and grandmother have all been diagnosed of a condition early and have then died.
This would ring alarm bells in anybody who was in a genetics organisation.
There is definitely a pattern.
The pattern we are seeing in this family is that not only it is female to female inheritance but it is also female to male.
An autosomal dominant condition.
A parent passes on one or other of each pair of their chromosomes to a child - which one they pass on is due to chance. There are therefore four possible combinations of chromosomes which the children of this couple could inherit.
Here are the four possible combinations of chromosomes. When a child inherits the chromosome with the altered gene, he or she has inherited the risk for the condition. When a child inherits the chromosome with the usual gene from their parent who has the condition, he or she has not inherited this risk.
As each one of the four possible outcomes shown here is equally likely, in each pregnancy there is a 1 in 2 (50%) chance that a child will inherit the autosomal dominant condition.
It can sometimes be important to explain to parents that as chance has no memory, the 1 in 2 probability of inheriting the gene for the condition applies to each child, irrespective of how many children they may already have who have or do not have the condition.
In patients with Familial Alzheimer’s disease we know that this has an early on-set and as many as 50 per cent of the cases are now known to be caused by defects in three specific alleles which are located on three different chromosomes. One of the things that is really important is that what we know is that Familial Alzheimer’s disease is an autosomal dominant inherited condition but we also know that in many families whilst the alteration is very clearly a dominant condition, where that alteration actually occurs can be very different between families. It is quite important that blood for DNA is taken from people who have got the condition so that if somebody else in the family gets the condition, you can actually be looking at the same place where the alteration is taking place on the chromosomes.
Without this DNA sample from the family members, it is really difficult to say that that is the alteration that has gone on to cause this particular individual to have this inherited type of Alzheimers.
One of the things to say is that because this particular type of Alzheimers is an autosomal dominant inherited condition, only one of the parents needs to have this alteration for the person to develop early on-set Alzheimers. One of the key things about early Familial Alzheimer’s disease is that it tends to be very early, normally in somebody under the age of 40.
However, there are forms of other inherited forms of dementia and dementia type conditions and sometimes we may see somebody in a family who has an specific condition but we cannot see it in the parents and therefore we may question whether it is an inherited condition.
For example, sometimes a known inherited condition may suddenly appear in a family. We need to be aware that there are some conditions, and Tay Sachs is a good example of that, where the conditions are inherited by an autosomal recessive condition.
In an autosomal recessive condition both parents would be carriers of the alteration but neither of them would exhibit the clinical symptoms of the condition.
What we know in this Tay Sachs pedigree that both mom and dad are carriers of this condition and when you are drawing a pedigree this is the way you would identify a carrier.
It also means that we need to be considering the other members of the families. Has the mother received the autosomal recessive alteration from her mom or dad, and therefore what is the situation for her brother and any subsequent children that her brother may have? The same for the father and his sister.
It is important to note that in autosomal recessive conditions whilst the mother is a carrier for the condition and has married the father who is also a carrier, for the brother and sister of both the mom and dad, the chance of them also marrying somebody who is carrying the recessive condition is incredibly low.
You may find that the chance of them being carriers of an autosomal recessive condition in both situations, is very low and means they or their children are only at the same risk as the general population. Although the brother of the mother and the sister of the dad may be carriers, the chance of their children also getting the condition is rare.
In this animation, each parent is a carrier for the same autosomal recessive condition.
A parent passes on one or other of each pair of their chromosomes to a child - which one they pass on is due to chance. There are therefore four possible combinations of chromosomes which the children of this couple could inherit.
The first combination shows a child who has inherited a chromosome with the usual gene from each parent: he or she will not have the condition and will not pass on the altered gene for the condition to his or her children. When a child inherits one copy of the usual gene and one copy of the gene alteration, he or she is a carrier for the condition like their parents. When a child has inherited a gene alteration from both parents, he or she will have the condition.
So where both parents are carriers, at conception each child has a 1 in 4 (25%) chance of inheriting two copies of the usual gene and of being neither a carrier nor having the condition. There are two chances out of four (50%) that at conception a child will inherit one copy of the usual gene and one copy of the altered gene and so will be a carrier for the condition. There is a 1 in 4 (25%) chance that a child will inherit a copy of the altered gene from each parent, and so inherit the condition.
As each one of the four possible outcomes shown here is equally likely, in each pregnancy there is a 1 in 4 (25%) chance that a child will inherit the autosomal recessive condition. It can sometimes be important to explain to parents that as chance has no memory, the 1 in 4 probability of inheriting two copies of the altered gene for the condition applies each time two parents who are carriers decide to have a child, irrespective of how many children they may already have who have or do not have the condition.
Here are some examples of autosomal recessive inheritance were we see dementia in individuals under 18 years of age. This is quite a problem area and is more often seen in paediatrics than in other areas.
Sporadic Alzheimer’s Disease
Although there is no evidence that autosomal dominant inheritance of altered genes causes late-onset Alzheimer's, genetics does appear to play a role in the development of this more common form of the disease. Research has found an increased risk for late-onset Alzheimer's in people who inherit one or two copies of a particular variation of an allele called apolipoprotein E (APOE) -- the variation known as APOE e4. Different variations, or alleles, produce variations in inherited characteristics, such as eye colour or blood type. In this case, the variations are in the APOE gene that directs the manufacture of apolipoprotein E, a protein that helps carry blood cholesterol throughout the body, among other functions. It is found in neurons and other supportive brain cells (called glia) of healthy brains, but it is also associated in excess amounts with the plaques found in the brains of people with Alzheimer's.
Researchers are particularly interested in three common alleles of the APOE gene: e2, e3 and e4. The finding that increased risk is linked with inheritance of the APOE e4 allele has helped explain some of the variations in age of onset of Alzheimer's disease based on whether people have inherited zero, one, or two copies of the APOE e4 allele from their parents. The more APOE e4 alleles one inherits, the lower the age of disease onset. The relatively rare APOE e2 allele may protect some people against the disease: It seems to be associated with a lower risk for Alzheimer's and a later age of onset if the disease does develop. APOE e3 is the most common version found in the general population and may play a neutral role in Alzheimer's risk.
The first altered allele to be linked to late-onset Alzheimer's was APOE-E4, identified in 1995. In the past several years, four other genes were identified. The latest research identified four new Alzheimer's genes— called MS4A, CD2AP, CD33, and EPHA1 — and helped confirm the role of two other genes, BIN1 and ABCA7. The findings doubled the number of genes alterations known to play a role in Alzheimer's disease, bringing the total to 10. Other genes are associated with the far less common early-onset Alzheimer's disease, which runs in families and arises in people younger than 50.
APOE-E4 appears to confer the greatest risk of developing Alzheimer's in old age, typically between the ages of 60 and 80. Inheriting a copy of the gene from one parent doubles or triples the lifetime risk that you might get the disease, though having the gene by no means guarantees that you will get Alzheimer's. Inheriting two copies of the gene, one from each parents, increases risk by five-fold.
All the genes appear to play a role in the way that the body processes cholesterol, a blood fat that is known to play a role in heart disease. They also appear to be linked to inflammation, which also plays a role in heart disease. Both inflammation and cholesterol metabolism are recognized as factors in Alzheimer's and other types of dementia as well.
Many of the conditions that are associated with childhood or adult onset dementia are also seen in individuals that have behavioual disorders or mental illness as a frequent presenting manifestation of the disease.
We do not expect you to be experts in understanding all of the causes of genetic conditions or the genetic on-set conditions in dementia. We want you to be alert to the clues that might indicate a genetic condition. This may be something that a patient may say to you, or it may be something that a family member may say to you. One of the things that you may be able to do is to re-assure that person that what they are describing (they may say both my mom and grandfather had dementia, I know I am going to get it) is whether it was mom’s dad who had the condition or in fact whether it was their father’s father who had the condition and therefore there is not a straight blood line in between grandfather, mom and the person who is talking to you.
It may be that they are telling you that dementia occurred when they were in their 70s, 80s or even older, where it is unlikely to be an inherited form of the condition. Quite often patients with dementia who have an inherited form of the condition, have other illnesses which are given a label and you will be able to clearly see the difference between an inherited form of dementia, however many people are very worried about getting dementia. If they have one family member who has got it, they may have concerns so they may ask you that information.
It is really important that you know why the general clues are of what may lead you to think that a condition might be an inherited type of condition.
You might then need to ask the right questions and the questions are things like ….
The information depends on the context and the reasons why you are connecting it. It is important to establish biological relationships. We are very aware these days, with extended and convoluted families that sometimes it can be quite difficult to establish the biological relationships. It is also important that we clarify the medical condition that people actually have because quite often people will say everybody in my family, for example, has got cancer and when you drill down it is very different types of cancer and therefore the inheritance pattern is unlikely.
It may be that when you are looking at people with Alzheimers or dementia, that there is a very clear difference between a vascular form of dementia and other types of old age on-set dementia.
We recommend that you draw our a three generational family history and if that gives you some alarms, then you might want to action it.
It is also important that you try to collect the information, including their full real name, not their known by name, their date of birth or the age in which they were diagnosed, the dates of death or the age approximately when they died and particularly the medical information. Age of diagnosis is a really important signal as to whether somebody may have a particular condition.
Please also make sure that when drawing the pedigree, and here is an example of the different symbols that universally are used to draw out our a family tree, including the lines that connect individuals within the family – one of the things we suggest that when you are taking a family tree is you do it very systematically.
This looks like a very busy slide but you will see in numerical order the best way of drawing it. Taking the family history from your patient who is here with the arrow pointing at them, you take their husband/partner and their children in the first instance, and then build it up, identifying parents and then any siblings. You may then ask about their sibling’s partner and children, and then going up to the next generation. That may be as far as you need to go but there is a lot more information that you can glean but doing so in a systematic manner is terribly important.
As I have said within this presentation, three generational family history is really all you need to do. This slide shows all the other information that may be gathered if you refer your patient onto a specialist or Regional Genetics service.
Ensure that if you draw a pedigree, you date it, put your name on it as the person who has drawn it and where you are based, and also details of who the person is who has given the information.
Moving on, you can get information from the National Genetics and Genomics Education Centre. There is lots of information on their website and you can also get a template if you want to, through the enquiries desk, which will help you draw out an appropriate family history.
Most importantly is acting upon the information that you have.
Acting may be a number of things: you may want to go to a website for example.
On this particular website many genetic conditions are included in alphabetical order, with a whole range of information about the genetic conditions, which may give you a bit more information when you are answering some questions for your patients.
Including a factsheets at http://www.geneticseducation.nhs.uk/search/item/1292-1292-dementia
Most importantly is understanding why a patient wants to ask you the questions and also how they are going to respond when you are giving them information.
For example, these are some of the things that were said by family members who had a relative who had dementia and a discussion had taken place as to whether or not they wanted to know if they also carried an altered gene.
I think a very realistic comment was “my feeling is I’d only want to know if there’s something I can do about it”. Certainly in many discussions I have had with people over the last few years looking at dementia, until there is some really good way of preventing dementia or treating it in a very clear way, a lot of people really don’t want to know about it. I think for other people they are very scared that when something simple like “I can’t remember when I’ve parked my car” happens, they therefore think this is it, I am going to get dementia, when actually it is just another senior moment that many of have us at a certain age.
The most important thing you may be able to do is to reassure. You may want to refer – to a GP or to a Clinical Genetics Service or to a dementia clinic, if there is one available. So actually seeking out the most appropriate service.
Make sure you go to trusted sources of information, because quite often the information that is available on the website is very suspect. Going somewhere like the Genetics and Genomics for Healthcare may help or to the Alzheimer’s Society where they have some fantastic resources.
As a note of interest, most Clinical Genetics departments have an on-call service where they will be able to advise you as to what you need to do.
As I said, the Alzheimer’s Society have got some great information about risk and developing dementia, and also some great information about the different types of dementia. It is really important to know the type of dementia that your patient has got, as we are fairly clear that the inherited forms of dementia have different risk factors.
If you do want to contact Regional Genetic Service, there is a list of ‘phone numbers here. Please contact your local one because they will have some information.
There is more information available on the genetics website.
I hope you have found this presentation useful. Please feel free to use any of the slides that are available here as they are all available resources.
There are also some further animations around on autosomal dominant and autosomal recessive conditions that you can download to use, and some videos on how to draw taking a family history. There are worksheets that can be used for teaching if you are using them in any session.
I hope that has been useful, please contact us via genetics enquiries if you wish to leave a comment or request further information
