To assess the contribution of apolipoprotein E (APOE) ε3 and ε4 alleles to the incidence of Alzheimer's disease (AD) and all-cause dementia, highlighting their significance in disease risk.
Key Findings:
Up to 93% of neuropathologically confirmed AD cases were attributable to APOE ε3 and ε4 alleles.
PAFs for clinically diagnosed AD were 72% in FinnGen and 76% in UK Biobank.
For all-cause dementia, PAFs were 44% in UK Biobank and 46% in FinnGen.
85% of cerebral amyloidosis detected in the A4 Study was attributed to ε3 and ε4 carriage.
Additional analyses suggested that ε3 contributed meaningfully to disease burden alongside ε4.
Interpretation:
The findings highlight the significant role of APOE genetic variants in the development of Alzheimer's disease and dementia, suggesting a need for targeted interventions that address both ε3 and ε4 alleles.
Limitations:
Estimates were imprecise due to the rarity of ε2/ε2 homozygotes affecting PAF calculations, which may influence the reliability of the findings.
Study population predominantly of European ancestry may limit generalizability to other populations.
Variability in outcome ascertainment and potential misclassification in clinical diagnoses could affect the study's conclusions.
Conclusion:
Prioritizing interventions targeting both APOE ε3 and ε4 could facilitate dementia prevention efforts.
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