On 9 January, an international team of researchers from the UK, Finland and Norway published an article on the proportion of Alzheimer’s disease attributable to apolipoprotein E in the npj dementia journal. The authors note that variation in the APOE gene strongly affects Alzheimer’s disease (AD) risk, but that 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. To estimate the extent to which clinically diagnosed AD, AD neuropathology and all-cause dementia are attributable to common APOE alleles, the team analysed four large datasets. They used linked electronic health records to ascertain AD and all-cause dementia in two cohorts aged 60 and over: 171,105 participants from UK Biobank and 289,150 participants from FinnGen. They examined amyloid-β positivity using amyloid positron emission tomography scans from 4,415 participants in the A4 Study.
They also analysed neuropathologically confirmed AD in the Alzheimer’s Disease Genetics Consortium, comparing cases with pathology-negative, cognitively intact controls (N=5,007). In each analysis, they estimated outcome risk among carriers of APOE risk alleles ε3 and ε4 relative to individuals with an ε2/ε2 genotype, then calculated attributable fractions for ε3 and ε4. For AD, attributable fractions ranged from 71.5% (95% confidence interval 54.9% to 81.7%) in FinnGen to 92.7% (82.4 to 96.5%) in the Alzheimer’s Disease Genetics Consortium. In A4, 85.4% (17.5 to 94.5%) of cerebral amyloidosis was attributable to ε3 and ε4. For all-cause dementia, attributable fractions were 44.4% (95% confidence interval 18.2% to 62.2%) in UK Biobank and 45.6% (30.6% to 56.9%) in FinnGen. The authors state that without strong underlying risks from APOE ε3 and ε4, almost all AD and half of all dementia would not occur and that intervening on APOE should be prioritised to facilitate dementia prevention. The article has been published open access and can be read here: