Researchers here provide data to support the claim that if everyone had the most favorable ε2 variant of the APOE gene, Alzheimer’s disease incidence would be a tenth of what it is now. APOE is involved in cholesterol trafficking and metabolism, and in recent years it has been suggested that the APOE variants connected with higher risk of Alzheimer’s cause dysfunction in microglia in the brain. Independently, that microglia become more inflammatory and dysfunctional with age has become an important line of research in the study of neurodegenerative conditions. Evidence strongly supports an important role for dysfunctional microglia in provoking the pathology associated with these conditions. Therapies focused on microglia have yet to emerge, but a number of approaches demonstrated in the laboratory and animal studies could lead to clinical trials given sufficient motivation and funding.
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 4,415 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 = 5,007).
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% in FinnGen to 92.7% in the ADGC. In A4, 85.4% of cerebral amyloidosis was attributable to ε3 and ε4. The proportions of all-cause dementia attributable to ε3 and ε4 in UKB and FinnGen were 44.4% and 45.6%, 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.
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