The proportion of Alzheimer's disease attributable to apolipoprotein E

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.

Keywords: Diseases; Genetics; Medical research; Neurology; Neuroscience; Risk factors.

Fig. 1. Proportions of AD and CAD that could be prevented by targeting molecular pathways related to the top ten genetic risk loci for each disease, ranked by size of PAF.

PAF—population attributable fraction Footnotes: ¹The APOE ε3 and ε4 estimate for AD is based on our PAF estimate from ADGC data, alongside statistics for other risk loci from GWAS. In the CAD GWAS, the PAF estimate for the APOE locus estimate was based solely on the odds of CAD for risk-conferring allele (C) of genotype rs7412, i.e. this estimate reflects the PAF for genotypes ε3/ε3, ε3/e4 and ε4/ε4 relative to ε2/ε2, ε2/ε3 and ε2/ε4 carriers (hence it may underestimate the contribution of APOE genotypes to CAD). ²Note that the confidence intervals for the PAF of AD attributable to ε3 and ε4 are not symmetric because PAFs plateau as they approach 100%.