How Do Genes Affect Alzheimer’s Risks?

By: Dr. Pascale Michelon

Although there is a strong association between the ApoE4 gene and the risk of developing late-onset Alzheimer’s Disease, researchers do not know what role this gene plays in the disease. A recent study provides new clues: in mice, ApoE4 damages the blood vessels that provide nutrients to the brain.

The role of genes in Alzheimer’s Disease (AD)
Early-onset AD is a rare form of AD that develops in people 30 to 65 years of age. Of all people having AD only 5% suffer from early onset. Some cases of early-onset, called familial AD, are inherited. These cases are caused by gene mutations on chromosomes 21, 14, and 1. If one parent has one of these gene mutations (and thus AD), offspring in the same generation have a 50/50 chance of developing AD.
Late-onset AD is the most common form of AD that develops after age 60. No gene has been found so far to be the cause of late-onset AD. However a predisposing genetic factor does appear to increase a person’s risk of developing AD. This increased risk is related to the apolipoprotein E (APOE) gene found on chromosome 19.

The apolipoprotein E (APOE) gene
The ApoE gene encodes a protein that helps regulate the levels of cholesterol and other lipids in the body. ApoE comes in several different forms. Three forms (or alleles) are the most common: ApoE2, ApoE3, and ApoE4.
People with AD are more likely to have an ApoE4 form than people who do not develop AD. ApoE4 occurs in about 40% of all people who have late-onset AD and only in 25 to 30% of the population. However, many people with AD do not have an ApoE4 allele.

A new study
Although there is a strong association between the ApoE4 gene and the risk of developing late-onset Alzheimer’s Disease, researchers until now did not know what role this gene may play in the disease. A recent mice study provides new clues.
Normally mice only have a single version of ApoE. For the study, the researchers worked with genetically engineered mice, including three lines that produce only human ApoE2, ApoE3 or ApoE4 and one line that lacks the ApoE gene.

They found that both in mice with the ApoE4 version or in mice that produced no ApoE at all, the blood-brain barrier was not working properly. The blood-brain barrier is a system along blood vessels that allows only some molecules to enter the brain (including oxygen and glucose) and prevents others from entering (such as bacteria). In the mice with the ApoE4 or no ApoE gene at all, the blood-brain barrier allowed harmful proteins to enter the mice’s brains.
After several weeks, the mice had loss of small blood vessels, loss of connections between brain cells and alterations in brain function.
The team also discovered that ApoE2 and ApoE3 help control  levels of cyclophilin A (CypA), an inflammatory molecule. In the blood vessels of mice that produce only ApoE4, the levels of this molecule were very high, which induced the destruction of protein components of the blood-brain barrier.

So what?
This study shows that damage to the brain’s vascular system may play a key role in Alzheimer’s disease. It points out potential mechanisms explaining the link between vascular deficits (e.g., strokes) and Alzheimer’s Disease as well as  between vascular risk factors (such as diabetes or high-blood pressure) and Alzheimer’s risk factors.
Although confirmation that similar mechanisms happen in the human brain is still needed, such study underlines the potential value of treatment reducing vascular risks factors, especially to lower the risks of Alzheimer’s Disease in people carrying the ApoE4 gene.

Reference: Bell, et al. (2012). Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature, May, doi:10.1038/nature11087.

2 comments on “How Do Genes Affect Alzheimer’s Risks?

  1. Pingback: Alzheimer’s Progression Less Agressive After 80 | The Memory Practice

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