APOE genotype, family history of dementia, and Alzheimer disease risk: a 6-year follow-up study.

BACKGROUND: Both family aggregation and apolipoprotein E (APOE) epsilon4 allele are well-known risk factors for dementia, but the relation between these two factors remains unclear.

OBJECTIVE: To explore whether the risk of dementia and Alzheimer disease (AD) due to a positive family history is explained by APOE genotypes.

DESIGN: Community-based cohort study.

SETTING: The Kungsholmen district of Stockholm, Sweden.

PARTICIPANTS: A total of 907 nondemented people 75 years or older, followed up for 6 years to detect incident dementia and AD cases according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition.

MAIN OUTCOME MEASURES: Risk of dementia and AD by Cox proportional hazards models after controlling for several potential confounders.

RESULTS: Subjects who had at least 2 siblings with dementia were at an increased risk of AD. Individuals with both APOE epsilon4 allele and at least 2 affected first-degree relatives had a higher risk of dementia and AD compared with those without these 2 factors. Similar results were obtained for history of dementia separately in parents or siblings. Among the epsilon4 allele carriers, subjects with 2 or more first-degree demented relatives had increased risk of dementia and AD, whereas no increased risk was detected among non-epsilon4 carriers.

CONCLUSIONS: Family history of dementia was associated with an increased risk of dementia and AD in this very old population, but only among APOE epsilon4 carriers. This suggests the existence of other genetic or environmental risk factors that may be active in the presence of the APOE epsilon4 allele.