APOE and Alzheimer disease: a major gene with semi-dominant inheritance.
Level 4 - case-series / case-control
Case-control study data combined with epidemiological incidence curves to calculate lifetime risk
PubMed 21556001 · doi:10.1038/mp.2011.52
What was done
The authors calculated lifetime risks of Alzheimer disease stratified by APOE genotype, sex, and age. They combined genotype distributions from 7,351 cases and 10,132 controls of Caucasian ancestry with population-based incidence rates from Rochester, Minnesota (USA) and the PAQUID cohort (France).
What was found
At age 85, unstratified lifetime risk of Alzheimer disease was 11% in males and 14% in females. Using Rochester incidence data, lifetime risk at age 85 was 51% for APOE 4/4 males, 60% for APOE 4/4 females, 23% for APOE 3/4 males, and 30% for APOE 3/4 females. Using PAQUID incidence data, lifetime risk at age 85 reached 68% for APOE 4/4 females and 35% for APOE 3/4 females. Stratification by age groups demonstrated that APOE4 is a risk factor for both early-onset and late-onset Alzheimer disease.
Why it matters
This study shows that APOE4 functions more like a major semi-dominant gene with high lifetime penetrance, comparable to BRCA1 in breast cancer, rather than a typical low-risk GWAS allele.
Limits
The analysis was restricted exclusively to individuals of Caucasian ancestry, limiting generalizability to other populations. The results rely on mathematical risk modeling combining retrospective case-control frequencies with regional incidence datasets rather than direct lifetime prospective cohort observation. Estimates for APOE2-containing genotypes were not reported in the abstract.
Cited by
- supports Individuals with no copies of the ApoE4 allele (such as ApoE 3/3) have an estimated lifetime risk of Alzheimer's disease of about 9%.