The APOE4 gene variant increases a person's risk of Alzheimer's disease exponentially, though a new protective mutation has been discovered to protect against this risk.
Although the APOE4 variant is the greatest risk factor of late-onset Alzheimer's, the most common form of dementia, not all who carry the high-risk variant will develop the disease. This phenomenon has interested scientists for decades, prompting a global consortium to investigate the genetic cause of this variability. The research team, led by Michael Greicius, professor of neurology at Stanford Medicine, California, found that a mutation called R251G reverses the risk posed by APOE4.
Professor Greicius said, 'It probably increases your risk [of Alzheimer's] two or threefold if you have one APOE4 copy, and if you have two APOE4 copies, it probably increases your risk about tenfold.' He added, 'maybe one in 1000 people who carry that high-risk gene also carry on the same copy of the gene a protective variant that essentially takes the high risk and cuts it.'
The global consortium analysed the genome of over 500,000 individuals who either had Alzheimer's disease or were a healthy control. They found that individuals who carried the APOE4 variant as well as the R251G mutation had a far lower incidence of Alzheimer's disease than those with APOE4 alone.
While all individuals express APOE, a protein involved in cholesterol trafficking in the brain and body, there are three different variants of the gene: APOE2, APOE3 and APOE4. The most common is APOE3, which does not influence the risk of Alzheimer's disease, whereas the presence of APOE2 reduces the risk of Alzheimer's disease. Around 25 percent of individuals with European ancestry carry the APOE4 gene, with an increased risk of Alzheimer's disease.
The R251G mutation on the APOE4 gene variant causes a single amino acid change in the APOE protein, which is made up of around 300 amino acids in total. This protective variant is on the part of the protein that binds to lipids like cholesterol or other fats and neutralises the risk normally caused by APOE4 variant.
'Identifying genetic variants counterbalancing the risk of APOE4 may shed new light on its role in Alzheimer's disease development' said Dr Yann Le Guen, co-lead author of the study, 'This finding could help develop new drugs mimicking the effect of the protective genetic variant to reduce the risk of disease.' Therefore, other individuals with Alzheimer's disease may benefit from future therapies inspired by this finding.
The study was published in JAMA Neurology.
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