The latest development in the ongoing pursuit of a cure for Alzheimer’s disease offers the sort of prescription that many dementia sufferers and their caregivers may greet with a certain sanguinity: “Well . . . duh!” Indeed, the British scientists who last week announced the breakthrough seemed to be wondering out loud, “Why didn’t we think of this before?”
Because a single gene (APOE) has long been associated with the development of Alzheimer’s, researchers at University College London (UCL) decided to look more closely at the genetic makeup of people who have been diagnosed with the disease. The results of their study suggest that a little gene editing could go a long way toward preventing the illness.
We all carry two APOE genes, but it’s the specific variants, or alleles, that often determine an individual’s risk of developing dementia. Those with the E4 variant, for instance, are much more likely to succumb to major cognitive dysfunction than people carrying the E2 type, notes lead study author Dylan Williams, PhD, a genetic epidemiologist fellow at UCL. But the risk rises even further when E4 is combined with the E3 allele.
“When we consider the contributions of E3 and E4, we can see that APOE potentially has a role in almost all Alzheimer’s disease,” he explains. “Consequently, if we knew how to reduce the risk that the E3 and E4 variants confer to people, we may be able to prevent most disease from occurring.”
Williams and his team arrived at this conclusion after analyzing four major studies involving more than 450,000 participants. Reporting in the journal npj Dementia, the researchers determined that somewhere between 72 and 93 percent of the individuals diagnosed with Alzheimer’s carried the E3 and E4 variant. Block those genes with various gene-editing tools, the theory goes, and you could prevent the vast majority of dementia cases.
While conceding that other nongenetic factors, such as diet and fitness, often determine whether an individual may develop the disease, Williams touts gene editing as a promising — and underappreciated — clinical approach to treating Alzheimer’s.
“There has been major progress in recent years in gene editing and other forms of gene therapy to target genetic risk factors directly,” he says. “Intervening on the APOE gene specifically, or [on] the molecular pathway between the gene and the disease, could have great, and probably under-appreciated, potential for preventing or treating a large majority of Alzheimer’s disease.”
It may be underappreciated for a reason. As Ian Sample reports in The Guardian, messing with the APOE gene, which plays a major role in distributing cholesterol and fats throughout the body — including the brain — could become more of a problem than a solution. Plus, almost all of us carry one or both of the risky variants, meaning that any effort to significantly slow the spread of the disease would require a widespread campaign to convince people to submit to gene editing.
And are people even prepared to undergo genetic testing to learn whether they have the riskiest E3-E4 combo of APOE variants? This could be helpful for younger people who display symptoms of dementia or come from a family with a history of young-onset Alzheimer’s, but it is generally not helpful for older individuals, according to the Mayo Clinic. Healthcare providers typically do not recommend genetic testing for these patients. It doesn’t reliably predict a diagnosis, and there are other diagnostic approaches that are more accurate.
And, as a recent study in The Lancet Healthy Longevity notes, discovering your genetic risk factors without proper supervised preparation can trigger anxiety, depression, and other psychological issues. Demand for this information, however, has been rising, the authors report, and the information can appear on a patient’s medical records with or without their consent.
“Given the growing number of people who will learn their APOE results,” they write, “it is imperative to understand the psychological impact of receiving genetic information and best practices for communicating results, particularly in cognitively unimpaired adults.”
Tim Frayling, PhD, a professor of human genetics at the University of Geneva, points out that these genetic findings are not particularly meaningful. “People should not worry if they have [one of] the risk versions of the gene,” he tells The Guardian, “because 99.4 percent of us do.”
I’m not sure if that’s reassuring or depressing, but it probably helps explain why nobody ever thought about curing Alzheimer’s with gene editing before. Duh!
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