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Variants in a gene called APOE have long been associated with Alzheimer’s disease (AD) and dementia, but a new study suggests we’ve been seriously underestimating their effect. Per this analysis, two APOE gene variants could be implicated in up to 93 percent of AD cases and 45 percent of overall dementia cases, suggesting strongly that drug research should be looking squarely in the direction of APOE.
The rest of this article is behind a paywall. Please sign in or subscribe to access the full content.There are three common alleles of the APOE gene, called ε2, ε3, and ε4. Since each of us carries two copies of APOE, that means six possible combinations of these three alleles.
The gene codes for a protein called apolipoprotein E (APOE). As early as the 1990s, some forms of APOE protein were found to be strongly associated with the risk of developing AD in later life.
But since then, this gene hasn’t necessarily had the attention of the global dementia research community in the way we might expect. We asked Dr Dylan Williams, lead author of the new study from the UCL Division of Psychiatry and Unit for Lifelong Health and Ageing, why that is.
The full importance of APOE has probably not been sufficiently recognised by dementia researchers.
Dr Dylan Williams
“First, since the discovery of APOE’s links to AD from the late 1980s to mid 1990s, research in the field has been predominated by interest in addressing the two core hallmarks of the disease that are observed in the brains of AD patients,” Williams explained. “These are sticky plaques comprised of a protein called β-amyloid between brain cells, and tangles of another protein called tau which form within brain cells.”
Over the years, a lot of research has focused on the push and pull between theories surrounding these two proteins: which is the more important to AD pathology, and which should be the focus to slow or prevent the development of disease? APOE and its protein were sidelined.
“Second, the full importance of APOE has probably not been sufficiently recognised by dementia researchers,” Williams added. “Third, it is possible that past attempts to address APOE-related risk therapeutically were challenging – i.e. historically, maybe APOE was not a very tractable drug target, especially given that it probably needs to be targeted within the central nervous system and not the body more widely.”
Previous pharmaceutical technology may not have been up to the task, but that doesn’t mean that it’s not now time for another look at APOE.
“Of particular relevance here are vast improvements in the prospects for gene therapy (editing / silencing / transfer approaches) in the past decade or so,” Williams told IFLScience. “I hope that our research helps to motivate much more activity in this area.”
APOE’s contribution to AD risk
Looking at the results of the new study led by Williams along with colleagues at UCL and in Finland, it’s easy to see why the team believes the contribution of APOE has been underestimated.
The study was three-fold, using electronic medical records, brain scans, and the results of postmortem examinations across a range of large, existing AD and dementia research cohorts. In each case, the team used the available data to estimate the risk of developing AD or dementia in carriers of two APOE alleles: ε3 and ε4.
Expectations and findings seldom align really well in research, so it was a nice surprise in that sense!
Dr Dylan Williams
For a long time, the prevailing view was that people with one or two copies of the ε2 allele had some protection against dementia. The ε4 allele, conversely, was the one most highly associated with AD. But where does that leave ε3?
“The view that APOE ε2 is associated with lower risk and APOE ε4 with higher risk (relative to people with ε3/ε3) has led to a longstanding misperception among dementia researchers that ε3 itself is neutral with respect to Alzheimer’s,” Williams told IFLScience. In reality, he explained, it makes more sense to think of AD risk as a spectrum: carriers of ε2 are at lower risk, carriers of ε3 are at intermediate risk, and carriers of ε4 are at higher risk.
Previous research has focused solely on ε4. Williams used the analogy of research into lung cancer and smoking: looking only at ε4 in Alzheimer’s would be like looking only at heavy smokers and lung cancer risk, while ignoring moderate smokers and non-smokers. You wouldn't be seeing the full picture.
Without the contribution of APOE ε3 and ε4, the team concluded based on their analysis, “almost all AD and half of all dementia would not occur.” In numbers, they estimate that 72-90 percent of AD cases and 45 percent of all-cause dementia cases would not have happened, were it not for these two alleles.
“A small number of astute investigators had essentially inferred what we are showing at least 20 years ago, though they were not able to show this with direct empirical data,” Williams told IFLScience. “So it was reassuring to see the fractions we estimated align with the expectation of my astute forebearers in dementia research. Expectations and findings seldom align really well in research, so it was a nice surprise in that sense!”
A fresh approach to AD treatment
What all this means going forward, according to the team, is that much more attention should be paid to the APOE pathway when it comes to drug development. We’ve seen some new AD drugs making big splashes in recent years, but that has not come without controversy. Perhaps a new target and a fresh approach is what is really needed.
“The recently licensed anti-amyloid therapeutics show, at best, limited effectiveness at slowing disease in AD cases, despite being brilliant at doing what they are supposed to do in molecular terms (clearing β-amyloid from the brains of AD patients),” said Williams. “Moreover, there are still reasons to doubt whether these drugs are effective at all.”
“Hence, we really need to be exploring many different therapeutic options for AD,” he added, calling APOE a “natural target crying out for much more research activity.”
It’s work that’s already underway. Williams told IFLScience there are plans to investigate the role of APOE in AD in a more ethnically diverse cohort, since the current study included primarily people of European descent. There’s also a lot to unpack about the environmental and other genetic factors that interlink with APOE – not absolutely everyone with a high-risk APOE genotype will get dementia, and we need to understand why that is.
Some of the support for this work is coming from Alzheimer’s Research UK. In a statement, Director of Research Dr Sheona Scales said, “Alzheimer’s Research UK is delighted to support Dr Williams as he continues to investigate how genetics alongside environmental and societal factors influence dementia risk, which will ultimately bring us closer to a cure.”
The study is published in the journal npj Dementia.
