Most Alzheimer's disease cases would not occur without the underlying genetic risk conferred by apolipoprotein E ε3 and ε4 alleles, according to a population-based analysis of more than 470,000 participants. Researchers estimated that up to 93% of neuropathologically confirmed Alzheimer's disease was attributable to these common genetic variants, with roughly half of all-cause dementia similarly linked to apolipoprotein E variation.
The analysis, published in npj Dementia, drew on four data sources: UK Biobank, FinnGen, the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Study, and the Alzheimer's Disease Genetics Consortium (ADGC). Patients were aged 60 years or older at baseline or outcome ascertainment. Alzheimer's disease (AD) and dementia were identified through linked electronic health records, imaging-based biomarkers, or postmortem neuropathological assessment. Apolipoprotein E (APOE) genotypes were derived from standard single-nucleotide polymorphisms, with ε2/ε2 homozygotes serving as the reference group to calculate population attributable fractions (PAFs).
AD risk increased progressively across APOE genotypes. For clinically diagnosed AD, PAFs for ε3 and ε4 combined were 72% in FinnGen and 76% in UK Biobank. Among ADGC patients with neuropathologically confirmed AD, 93% of cases were attributable to these alleles. In the A4 Study, 85% of cerebral amyloidosis detected on positron emission tomography was attributed to ε3 and ε4 carriage. For all-cause dementia, PAFs were 44% in UK Biobank and 46% in FinnGen. Additional analyses suggested that ε3 contributed meaningfully to disease burden alongside ε4.
The researchers reported several limitations. Estimates were imprecise in some analyses because ε2/ε2 homozygotes are uncommon, making PAF calculations sensitive to variation in the reference group. Most patients were of European ancestry, which may limit generalizability to other populations. Outcome ascertainment differed across cohorts, and reliance on clinical diagnoses in some datasets may have introduced misclassification compared with neuropathological confirmation. PAFs may also overlap in multifactorial diseases and are influenced by study design, follow-up duration, and selection effects.
Comparative analyses using genome-wide association study data indicated that no other common genetic locus accounted for a similar proportion of AD burden. "Intervening on APOE should be prioritised to facilitate dementia prevention," wrote lead study author Dylan M. Williams, PhD, of the Division of Psychiatry and the Unit for Lifelong Health and Ageing at University College London, and colleagues.
The authors declared no competing interests.
Source: npj Dementia