New research published in npj Dementia suggests that most cases of Alzheimer disease (AD) and nearly half of all dementia diagnoses may be attributable to common variants of the APOE gene, underscoring the critical role of APOE in disease risk and prevention strategies.

Researchers pooled data from 4 large cohorts—UK Biobank (UKB), FinnGen, the A4 Study, and the Alzheimer’s Disease Genetics Consortium (ADGC)—to quantify the contribution of the APOE ε3 and ε4 alleles to AD and dementia burden. Risk estimates were compared against individuals with the ε2/ε2 genotype, which is considered protective.

The following key results were reported:

  • The APOE ε3 and ε4 alleles accounted for 71.5% to 92.7% of AD cases across all cohorts, with the highest attributable fraction seen in autopsy-confirmed cases (ADGC).
  • In the A4 Study, 85.4% of instances of cerebral amyloidosis detected via PET imaging were linked to APOE ε3 and ε4 alleles.
  • For all-cause dementia, the APOE ε3 and ε4 alleles were responsible for 44.4% of cases in the UK Biobank and 45.6% in FinnGen.

These findings highlight the central role of APOE in AD pathogenesis and support the prioritization of APOE-targeted interventions. The researchers conclude that, in the absence of APOE ε3 and ε4-related risk, the majority of AD cases—and a substantial proportion of all-cause dementia—would not occur. This suggests that therapies aimed at modifying APOE-related pathways could significantly reduce the global burden of dementia.

Source: Williams, DM, Heikkinen S, Hiltunen M, et al. The proportion of Alzheimer’s disease attributable to apolipoprotein E. npj Dement. 2026;2(1). doi.org/10.1038/s44400-025-00045-9