The proportion of Alzheimer disease attributable to Apolipoprotein E

Variation in the APOE gene strongly affects Alzheimers disease (AD) risk. However, the proportion of AD burden attributable to this variation requires clarification. 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-{beta} positivity from amyloid positron emission tomography scans in 4,440 participants of the A4 Study. Third, we analysed data from the Alzheimers Disease Genetics Consortium (ADGC), where neuropathologically-confirmed AD cases were compared to pathology-negative, cognitively intact controls (N=5,007). In each analysis, we estimated outcome risk among carriers of APOE risk alleles {varepsilon}3 and {varepsilon}4, relative to individuals with an {varepsilon}2/{varepsilon}2 genotype, and calculated attributable fractions to show the proportions of the outcomes due to {varepsilon}3 and {varepsilon}4. For AD, fractions ranged from 71.5% (95% CI: 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 {varepsilon}3 and {varepsilon}4. The proportions of all-cause dementia attributable to {varepsilon}3 and {varepsilon}4 in UKB and FinnGen were 44.4% (95% CI: 18.2%, 62.2%) and 45.6% (30.6%, 56.9%), respectively. Without strong underlying risks from APOE {varepsilon}3 and {varepsilon}4, almost all AD and half of all dementia would not occur. Intervening on apolipoprotein E should be prioritised to facilitate dementia prevention.