How is our genetic make-up linked to the risk of developing dementia? And how does it affect disease progression?
Answering these questions could be key to developing new treatments. However, the diseases that cause dementia are extremely complex. To date we have only identified a few genes that can directly cause dementia. Researchers estimate that 25% of people diagnosed with dementia have a strong family history. Nonetheless, only 1% of people directly inherit a genetic mutation that causes early-onset dementia (symptoms appear before the age of 65). This is likely due to a complex interplay between genetic, environmental and other risk factors in dementia.
One of the genes that can influence risk of late-onset Alzheimer’s disease (onset after the age of 65) is the Apolipoprotein E gene (ApoE). ApoE is a lipoprotein that is found in the liver and macrophages (a type of white blood cell), as well as the brain. In the brain ApoE is secreted by special cells (astrocytes) and signals through specific receptors on nerve cells. ApoE is thought to play a role in the clearance of amyloid beta from the brain. It is also involved in the regulation of lipid homeostasis, synaptic transmission, and inflammatory damage to the blood-brain barrier.
Everyone has 2 copies of the ApoE gene. However, there are different types of ApoE: ApoE2, ApoE3 and ApoE4. These types are commonly referred to as alleles. The risk for developing Alzheimer’s disease depends on which combination of alleles one inherits.
ApoE2 is the rarest form, and it has been shown to have protective properties. In fact, ApoE2 appears to reduce the risk of developing Alzheimer’s disease by about 40%.
ApoE3, which is the most common allele, does not appear to influence the risk.
The ApoE4 allele was discovered in 1993 and carrying one or two copies of ApoE4 increases the risk of developing Alzheimer’s disease by 3 to 12-fold relative to ApoE3 (Source). ApoE4 is present in 10 to 15% of people. It is associated with an earlier disease onset with more severe pathology. Interestingly, its influence can vary across gender, age, race and nationality. If you would like to find out more about the genetics of Alzheimer’s disease, the National Institute of Aging provides an informative fact sheet on this topic. There is also a support group for carriers of the ApoE4 allele who are looking for more information or other people in the same situation.
Currently there are drugs in development that may change the physical structure of ApoE4 so that it behave more like ApoE2. An alternative approach is looking to use gene therapy to insert ApoE2 genes into brains of people with ApoE4 genes. Furthermore, researchers are investigating whether the ApoE genotype can affect the effects of drugs and other therapies in development for Alzheimer’s disease. You can find out more here.
It is important to remember that the ApoE4 allele is just one of many risk factors that affect our risk of getting Alzheimer’s disease. There are complex interactions at play. Therefore, factors beyond this genetic predisposition need to be considered when attempting to understand the underlying mechanisms.