Study links variants in single gene to incidences of dementia
New research from UCL has identified variations in a single gene as an under-recognised target for dementia therapies.
The APOE gene has previously been identified as having a strong association with the commonest form of dementia, Alzheimerโs disease.
However, statistical modelling by the UCL team, focussing on combinations of the geneโs most common allele variants, provided further evidence of how it might impact dementias, they say.
The gene has three common allele variants โ ฮต2, ฮต3, and ฮต4 โ with all individuals carrying two APOE genes in one of six possible combinations.
As early as the 1990s, it was established that the risk of Alzheimerโs was greater among people who carried one or more ฮต4 APOE alleles than for those who carried two copies of the more common ฮต3 allele. Likewise, ฮต2 carriers were at less risk compared to ฮต3 carriers.
Based on their modelling, the researchers estimated that 72-93% of Alzheimerโs cases would not have occurred without the presence of ฮต3 and ฮต4 alleles of theย APOEย gene. They added that approximately 45% of all dementia cases would not arise without the geneโs influence.
These higher-than-previous estimates ofย APOEโs influence occurred in the latest study, said researchers, because they considered the individual roles of both ฮต3 and ฮต4 variants.
Lead author Dr Dylan Williams from UCLโs division of psychiatry and its unit for lifelong health and ageing said:ย โThe ฮต4 variant ofย APOEย is well recognised as harmful by dementia researchers, but much disease would not occur without the additional impact of the common ฮต3 allele, which has been typically misperceived as neutral in terms of Alzheimerโs risk.
โWhen we consider the contributions of ฮต3 and ฮต4, we can see thatย APOEย potentially has a role in almost all Alzheimerโs disease. Consequently, if we knew how to reduce the risk that the ฮต3 and ฮต4 variants confer to people, we may be able prevent most disease from occurring.โ
Their researchย published inย npj Dementia, included datasets from four large studies with more than 450,000 participants, allowing a more comprehensive approach that studied the individual contribution of each of the three APOE alleles.
The scientists said the size of the study enabled them to find numerous examples from the rarer group of individuals with two ฮต2 alleles and for the first time to use these as their low-risk baseline.
They estimated that between 72-93% of Alzheimerโs cases would not have occurred without the ฮต3 and ฮต4 alleles of theย APOEย gene, and that approximately 45% of all dementia cases would not arise without the geneโs influence.
โThe extent to whichย APOEย has been researched in relation to Alzheimerโs or as a drug target has clearly not been proportionate to its full importance,โ insisted Williams.
He added that intervention on theย APOEย gene or the molecular pathway between the gene and the disease, had great potential for preventing for treating a large majority of Alzheimerโs cases.
However, he added the caveat that the APOE gene should not be misrepresented as a sole cause. Even among people with two copies of the ฮต4 allele, the lifetime risk remained below 70%, he said.
โMost people with genetic risk factors likeย APOEย ฮต3 and ฮต4 wonโt get dementia in a typical lifetime, since there are complicated interactions at play with other contributing genetic and environmental risk factors,โ he explained.
โUnderstanding what modifies the risk people inherit from theirย APOEย genes is another crucial question for dementia researchers to grapple with.โ
Pic: Anna Shvets
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