Researchers based at University College London claim that the ε3 and ε4 variants of the APOE gene are responsible for most cases of Alzheimer’s disease.
As reported in npj Dementia, an analysis using individuals with two copies of the protective ε2 variant as a comparator, 71–93% of Alzheimer’s and cerebral amyloidosis was attributable to ε3 and ε4 and around 44% of dementia.
“When we consider the contributions of ε3 and ε4, we can see that APOE potentially has a role in almost all Alzheimer’s disease. Consequently, if we knew how to reduce the risk that the ε3 and ε4 variants confer to people, we may be able prevent most disease from occurring,” said lead researcher Dylan Williams from the UCL Division of Psychiatry and Unit for Lifelong Health and Ageing at UCL.
The APOE ε4 variant, carried by around 25% of Americans, is a known risk factor for Alzheimer’s disease. Only around 2.3% of people in the U.S. carry two copies of ε4 but 22-23% of the population carry one copy. Those homozygous for ε4 can have as much as a 15% increase in risk for Alzheimer’s compared to the general population risk.
The APOE ε2 variant is rare and protective. Estimates suggest up to 13% of people carry one copy of the allele, with only around one percent of people carrying two, but the large majority of the population (up to 65%) have two copies of the ε3 gene.
In the past, most studies have used ε3/ε3 to denote standard risk, but in this study the authors chose to use ε2/ε2 as a control.
The researchers used data from the UK Biobank, FinnGen, the A4 Study (including people with asymptomatic Alzheimer’s) and the Alzheimer’s Disease Genetics Consortium (ADGC) study including around 470,000 people in total, almost all of whom were of European or closely related ancestry.
The investigators calculated attributable fractions to show which outcomes were linked to ε3 and ε4 versus ε2. In the Finnish FinnGen study, about 72% of Alzheimer’s cases were linked to the ε3 and ε4 forms of APOE versus 93% of the ADGC study. In the A4 trial, about 85% of amyloid build‑up in the brain was linked to ε3 and ε4. In UK Biobank and FinnGen combined, about 44% and 46% of all dementia cases, respectively, were linked to ε3 and ε4.
The study calls into question whether ε3 should be used to indicate neutral risk and suggests it should be treated more as a risk allele, albeit carrying a lesser risk than ε4. However, as people with two copies of the ε2 allele have significantly lower risk for Alzheimer’s than most people this comparison accentuates the apparent risk linked to carriage of ε3 and ε4.
Expert analysis of this paper is mixed and points out that APOE risk alleles are only one aspect of Alzheimer’s and dementia risk and that lifestyle also contributes. They also point out that the risk conveyed by the different APOE alleles varies depending on the population being analyzed so risks in people who are not of European origin may vary from those seen in this study.
