Influence of Alzheimer Disease Family History and Genetic Risk on Cognitive Performance in Healthy Middle-Aged and Older People

Objectives: Identification of risk factors for Alzheimer disease (AD) is critical for establishing effective diagnostic and therapeutic strategies. Carrying the epsilon 4 allele of the apolipoprotein E gene (APOE4) and having a family history of the disease are two such factors, with family history risk reflecting additional yet unknown or rarely studied genetic and perhaps nongenetic risks. Our aim was to determine the influence of APOE genotype and family history status on cognitive performance in healthy individuals. Design: Longitudinal study. Setting: Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles. Participants: Seventy-two cognitively healthy middle-aged and older people (mean age +/- SD: 62 +/- 9 years). Measurements: Neuropsychological examinations at baseline and after 2 years. Results: Subjects with a family history of AD had lower baseline scores in processing speed, executive functioning, memory encoding, and delayed memory when compared with those without a family history. The family history risk factor did not influence degree of cognitive decline over time. By contrast, baseline cognitive performance did not vary according to APOE4 carrier status. Non-APOE4 carriers showed improved cognitive performance in the memory domains at follow-up, while performance of APOE4 carriers did not change. Conclusions: Our data highlight the unique contributions of each risk factor to cognitive performance in healthy people. Both factors should be modeled in neuropsychological assessments of people at risk for AD. (Am J Geriatr Psychiatry 2012; 20:565-573)