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   Genetics of dementia   
      
      
   Genetics of dementia   
      
      
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   Many people with dementia are concerned that they have inherited the condition   
   and that they may in turn pass it on to their children. Also, family members   
   of people with dementia are sometimes concerned that they might be more likely   
   to develop dementia    
   themselves. Genes can play a role in the development of dementia, but their   
   effects are complicated and patterns of inheritance vary considerably. This   
   factsheet outlines the present state of knowledge about the genetics of   
   dementia.   
      
   Genes and inheritance   
   Characteristics that we have inherited from our parents are passed down to us   
   in the form of thousands of genes, the basic units of inheritance. Genes are   
   made from DNA and are found packed within each cell of our bodies on   
   structures called chromosomes.    
   We have 23 pairs of chromosomes and we inherit two copies of each gene, one   
   from each parent.   
      
   Genes provide the instructions needed to build our bodies. While many of our   
   genes are identical for all of us, some genes have slight variations that   
   account for the physical differences between people, and also underlie many   
   diseases. Some of these    
   variations between genes are common and are called genetic 'variants', while   
   others are rare and are called 'mutations'.   
      
   Some of our physical characteristics are inherited in a relatively simple way,   
   such as our blood group, which can be traced to a single gene. More often, our   
   individual qualities (eg height) reflect the complicated effects of many   
   different genes. Both    
   simple and complex (multi-gene) patterns of inheritance are seen in dementia.   
      
   Although genes are important in building our bodies, most of our physical   
   characteristics and the diseases we may experience are also greatly influenced   
   by our environment and lifestyle, which act to modify the effects of our   
   genetic inheritance.   
      
   For more information see factsheet 450, Am I at risk of developing dementia?   
      
   Genes and Alzheimer's disease   
   Alzheimer's disease is the most common form of dementia and, of all the main   
   types of dementia, the genetics of Alzheimer's is the best understood. We can   
   consider the disease to have two forms: the rare early onset Alzheimer's   
   disease, where first    
   symptoms appear before the age of 65; and the much more common late onset   
   Alzheimer's disease, where typically the first symptoms develop after this   
   age. These two types of Alzheimer's disease generally have different patterns   
   of genetic inheritance.   
      
   Early onset Alzheimer's disease   
      
   This form of Alzheimer's tends to cluster within families, sometimes with   
   several generations affected, in which case it is called familial disease. In   
   some of these cases, early onset Alzheimer's is caused by mutations in one of   
   three genes. These three    
   genes are the amyloid precursor protein gene (APP) and two presenilin genes   
   (PSEN-1 and PSEN-2). People with any of these extremely rare mutations tend to   
   develop Alzheimer's disease in their 30s or 40s.   
      
   The prevalence of the defective versions of these genes is as follows:   
      
   More than 80 known families worldwide have a mutation in the APP gene on   
   chromosome 21, which affects production of the protein amyloid. A build-up of   
   amyloid in the brain has been linked to Alzheimer's disease.   
   Nearly 400 known families worldwide carry a mutation in the PSEN-1 gene on   
   chromosome 14. This causes up to half of all early onset familial Alzheimer's   
   disease, with first symptoms from as early as 30 years of age.   
   Only a few dozen known families (mainly resident in the United States) have a   
   mutation in PSEN-2 on chromosome 1, causing early onset familial Alzheimer's   
   disease that starts slightly later than for PSEN-1.    
   It is important to note that these mutations are extremely rare and account   
   for fewer than one in 1,000 cases of Alzheimer's disease.   
      
   It is likely that all of those who inherit faulty versions of any of these   
   three genes will develop Alzheimer's disease at a comparatively early age. On   
   average, half of the children of a person with one of these rare genetic   
   mutations will inherit the    
   disease. People who do not inherit the mutation cannot pass it on.   
      
   If you have two or more close relatives (a close relative is defined as a   
   parent, brother or sister) who developed Alzheimer's disease before the age of   
   60, your GP can advise you about genetic testing and counselling for these   
   rare mutations, and refer    
   you to a geneticist, if appropriate.   
      
   Late onset Alzheimer's disease   
      
   Late onset Alzheimer's disease is much more common than early onset   
   Alzheimer's disease and its inheritance follows a more complex pattern. This   
   means that having a relative with this form of Alzheimer's increases your own   
   chances of developing it, but    
   not in a predictable way.   
      
   A small but growing number of genes have now been identified which affect - to   
   different degrees - the chances of developing late onset Alzheimer's. The   
   effects of these genes are subtle, with variations acting to increase or   
   decrease the risk of    
   developing Alzheimer's disease, but not directly to cause it.   
      
   The gene with the greatest known influence on the risk of developing late   
   onset Alzheimer's disease is called apolipoprotein E (APOE). This gene is   
   found on chromosome 19 and comes in three forms, which by convention are named   
   with the Greek letter    
   epsilon (ε):   
      
   APOE ε2   
   APOE ε3   
   APOE ε4.   
   We all have two copies of the APOE gene, and these may be the same as each   
   other or different. Hence we each have one of the six possible combinations:   
   ε2/ε2, ε2/ε3, ε3/ε3, ε2/ε4, ε3/ε4 or ε4/ε4.   
      
   APOE ε4 is associated with a higher risk of Alzheimer's. About a quarter of   
   the general population inherits one copy of the APOE ε4 gene. This increases   
   their lifetime risk of developing Alzheimer's disease by up to four times.   
   About 2 per cent of the population gets a 'double dose' of the APOE ε4 gene -   
   one from each parent. This increases their risk of developing Alzheimer's   
   disease by about 10 times or more. However, even then, they are not certain to   
   develop Alzheimer's.   
   About 60 per cent of the population has a 'double dose' of the APOE ε3 gene   
   and is at 'average' risk. Up to half of this group develops Alzheimer's   
   disease by their late 80s.   
      
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