A GENE variant that ups your risk of developing Alzheimer’s disease in old age may not be all bad. It seems that young people with the variant tend to be smarter, more educated and have better memories than their peers.
The discovery may improve the variant’s negative image (see “Yes or no”). It also suggests why the variant is common despite its debilitating effects in old age. Carriers of the variant may have an advantage earlier in life, allowing them to reproduce and pass on the variant before its negative effects kick in. “From an evolutionary perspective it makes sense,” says at Rush University Medical Center in Chicago.
The “allele” in question is epsilon 4, a version of the apolipoprotein E gene (APOE). Having one copy increases the risk of developing Alzheimer’s at least fourfold compared with people who have other forms of the gene. A person with two copies has up to 20 times the risk.
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One big clue that epsilon 4 might be beneficial emerged several years ago, when Han’s team scanned the APOE genes of 78 American soldiers. All had suffered traumatic brain injuries, many while serving in Iraq. Sixteen had at least one copy of epsilon 4. Han’s team expected to find that these carriers would be in worse cognitive shape than their counterparts with different versions of APOE, given previous studies that showed elderly people with epsilon 4 fare worse after head injury. But the opposite was true: soldiers with the epsilon 4 allele had better memory and attention spans (Journal of Neurology, Neurosurgery & Psychiatry, ).
It wasn’t the first study to suggest that epsilon 4 may be beneficial to the young. Back in 2000, researchers showed that young women with epsilon 4 have IQs a few points higher than those with no copies of the variant and score 7 points higher on the non-verbal portion of a common intelligence test (Neuroscience Letters, vol 294, p 179). Then in the Czech Republic in 2001, researchers showed that 87 per cent of epsilon 4 carriers go on to university, compared with 55 per cent of people with another version of APOE. The last group were also more likely to drop out of school (Neuropsychobiology, ).
More recently, of the University of Sussex, UK, and Natalie Marchant at the University of California, Berkeley, have uncovered still more benefits for young people carrying epsilon 4. Those aged between 18 and 30 with the gene variant excelled at tasks requiring the frontal lobe, a brain region involved in higher cognitive skills. In particular, epsilon 4 carriers did better in a card game that asked them to remember a future plan while busy with another task (Neuropsychopharmacology, ).
Rusted suggests that epsilon 4 helps people focus on important information. But recalling something also requires you to tune out the irrelevant bits, an ability known to decline with age.
Perhaps, Rusted says, without this second capability, epsilon 4’s benefits fall by the wayside. Why it has a negative effect in old age, however, is still a mystery, although a study carried out by at the University of Oxford in 2009 offers a tentative, hypothesis.
Her team asked 20 to 35-year-olds to remember which pictures of animals or landscapes they had seen before, while having their brains scanned with functional MRI. It was an easy task and all performed equally well. But a brain region critical to memory lit up more strongly in epsilon 4 carriers than in the others, raising the intriguing possibility that carriers’ brains get overworked in early life, only to be worn out by the time they hit old age. MacKay wouldn’t go that far, but she says: “It’s possible that your brain is having to work harder when it’s younger and this may have consequences for later life.”
“Your brain may have to work harder when it’s younger and this may have consequences later”
Yes or No to knowing if you have epsilon 4?
When DNA co-discoverer James Watson published his genome in 2007, he left one tiny bit out: the piece that would have told him which version of the APOE gene he has. He opted not to know whether he was carrying the epsilon 4 version, which can vastly increase the odds of developing Alzheimer’s disease.
He’s not the only one to make an exception for APOE: Harvard University psychologist , one of several high-profile scientists planning to make his genome freely available as part of the , will follow Watson’s lead and keep his APOE sequence a mystery.
In contrast, genome pioneer has let the world know that he has one copy of epsilon 4, which also increases the odds of developing heart disease – and has started taking a cholesterol-lowering drug that he hopes may also delay Alzheimer’s.
Scientific celebrities aren’t the only ones who agonise over their APOE status. Anyone who has forked out a few hundred dollars to have their genome scanned can decide whether to find out if their APOE gene puts them at increased risk of Alzheimer’s.
Knowing your status may not be all bad, says of Boston University in Massachusetts, who over two years monitored how people reacted to finding out which version of the gene they have (The New England Journal of Medicine, vol 361, p 245). “By and large there were no catastrophic reactions,” he says. The only people whose mood changed much were those relieved to discover they didn’t have the risky variant.
If epsilon 4 does improve cognition in young adults (see main story) does that strengthen the case for knowing whether you carry that version?
Clare MacKay, who studies the effect of epsilon 4 on cognition at Oxford University, thinks not. “I wouldn’t want to know whether I’ve got one and I certainly wouldn’t want other people to know.” Her lab is forbidden from telling the volunteers their APOE status. “It will only be a good idea to know your APOE genotype when there’s something we can do about it,” she says.
