British researchers say their recent study showed the APOE gene was the major link to most cases of Alzheimer’s disease across four cohorts, and that its contribution to disease burden has been “long under-estimated”.
Their findings of their study of 470 000 older adults found that Alzheimer’s and nearly half of all dementia was associated with variations in the gene, reports MedPage Today.
Dylan Williams, PhD, of University College London, and co-authors wrote in npj Dementia that APOE3 and APOE4 were tied to 71.5% to 92.7% of the Alzheimer cases they studied.
In all-cause dementia, the two alleles were linked with 44.4% to 45.6% of cases.
The study estimated risks relative to APOE2, the variant that protects against Alzheimer’s.
“While the APOE4 variant is well recognised as harmful, much disease would not occur without the additional impact of the common APOE3 allele, which has been typically misperceived as neutral in terms of Alzheimer’s risk,” William noted.
“When we consider the contributions of APOE3 and APOE4, we can see that APOE potentially has a role in almost all Alzheimer’s disease.”
The APOE gene has three alleles – APOE2, APOE3 and APOE4. Everyone has two APOE genes, leading to six possible combinations of variants. The APOE3 variant is most common.
But people carrying at least one APOE4 allele have a higher risk of Alzheimer’s disease. Those who carry two alleles have the highest risk, leading some researchers to suggest that APOE4 homozygotes have a distinct, genetically determined form of Alzheimer’s.
Alzheimer’s and other dementia are not caused solely by the APOE gene, Williams emphasised. Most people with APOE3 and APOE4 “won’t get dementia in a typical lifetime, since there are complicated interactions at play with other contributing genetic and environmental risk factors”, he pointed out.
“Understanding what modifies the risk people inherit from their APOE genes is another crucial question with which dementia researchers must grapple,” he added.
The Lancet Commission on dementia, for example, has suggested that nearly half of dementia incidence could be prevented or delayed by improving modifiable risk factors.
“While the risk with any of the APOE3 and APOE4 variants is higher, these genes did not make Alzheimer’s disease inevitable and more than 98% of people without dementia also had one of these genes,” noted Gill Livingston, MD, of University College London, who wasn’t involved with the research.
“We know from other work that even people with the APOE4 variant, which is a higher risk, have a reduced risk if they tackle other modifiable risk factors,” Livingston posted on the UK Science Media Centre website. “The authors do not account for these in the analyses.”
Claiming that most Alzheimer’s cases wouldn’t occur without the contribution of APOE was a bit like saying most road traffic deaths wouldn’t occur without the contribution of cars, said geneticist Timothy Frayling, PhD, of the University of Geneva.
“People should not worry if they have the risk versions of the gene, because 99.4% of us do,” he wrote.
Williams and colleagues evaluated data from four cohorts to estimate the extent to which clinically diagnosed Alzheimer’s disese, Alzheimer’s neuropathology, and all-cause dementia were attributable to APOE variants.
They analysed electronic health record data from 171 105 older adults in the UK Biobank cohort and 289 150 older adults in the FinnGen study to determine Alzheimer’s and all-cause dementia diagnoses.
They also examined baseline amyloid PET scans of 4 415 participants in the A4 trial and analysed data from 5 007 participants in the Alzheimer’s Disease Genetics Consortium (ADGC) of autopsy-confirmed Alzheimer’s cases and controls to provide a comprehensive view.
“Clinically diagnosed Alzheimer’s disease without neuropathological confirmation is commonly misclassified (differential diagnoses with other causes of dementia being a major issue), and the presence of Alzheimer’s disease neuropathology in vivo does not always mean individuals will develop dementia,” Williams and co-authors noted.
The ADGC cohort of autopsy-confirmed Alzheimer’s had the highest fraction of cases attributable to APOE3 and APOE4 variants (92.7%, 95% CI 81.4%-96.5%). The APOE4 allele accounted for 56.9% of ADGC cases, while 35.8% were attributable to APOE3.
Few studies have evaluated whether APOE can be targeted.
LX1001, a gene therapy that uses a viral vector to drive expression of APOE2 into the central nervous system of APOE4 homozygotes, recently showed promise in a phase1/2 trial.
The study had several limitations, the researchers acknowledged. People of European ancestry made up most of the samples and results may not apply to other ethnic groups.
Attributable fraction estimates also were sensitive to study features like follow-up periods, the extent of outcome ascertainment, and selection bias.
“These could affect estimates in either direction,” Williams and co-authors observed.
Study details
The proportion of Alzheimer’s disease attributable to apolipoprotein E
Dylan Williams, Sami Heikkinen, Mikko Hiltunen, FinnGen, Neil Davies & Emma Anderson.
Published in npj Dementia on 9 January 2026-01-26
Abstract
Variation in the APOE gene strongly affects Alzheimer’s disease (AD) risk. However, the proportion of AD burden attributable to this variation requires clarification, which would help to elucidate the scope of strategies targeting apolipoprotein E (APOE) for AD prevention and treatment. We estimated the extents to which clinically diagnosed AD, AD neuropathology and all-cause dementia are attributable to the common APOE alleles in four large studies. First, we used data on 171,105 and 289,150 participants aged ≥60 years from UK Biobank (UKB) and FinnGen, respectively. AD and all-cause dementia were ascertained from linked electronic health records in these cohorts. Second, we examined amyloid-β positivity from amyloid positron emission tomography scans of 4415 participants of the A4 Study. Third, we analysed data from the Alzheimer’s Disease Genetics Consortium (ADGC), where neuropathologically confirmed AD cases were compared to pathology-negative, cognitively intact controls (N = 5007). In each analysis, we estimated outcome risk among carriers of APOE risk alleles ε3 and ε4, relative to individuals with an ε2/ε2 genotype, and calculated attributable fractions to show the proportions of the outcomes due to ε3 and ε4. For AD, fractions ranged from 71.5% (95% confidence interval: 54.9%, 81.7%) in FinnGen to 92.7% in the ADGC (82.4, 96.5%). In A4, 85.4% (17.5, 94.5%) of cerebral amyloidosis was attributable to ε3 and ε4. The proportions of all-cause dementia attributable to ε3 and ε4 in UKB and Fin-Gen were 44.4% (95% CI: 18.2%, 62.2%) and 45.6% (30.6%, 56.9%), respectively. Without strong underlying risks from APOE ε3 and ε4, almost all AD and half of all dementia would not occur. Intervening on APOE should be prioritised to facilitate dementia prevention.
MedPage Today article – Alzheimer’s Risk May Be Driven by a Single Gene (Open access)
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