Apolipoprotein E epsilon 4 allele and the lifetime risk of Alzheimer's disease. What physicians know, and what they should know

S. Seshadri, D. A. Drachman and C. F. Lippa
Department of Neurology, University of Massachusetts Medical Center, Worcester, USA.

BACKGROUND: Published studies now show a clear association between Alzheimer's disease (AD) and the apolipoprotein E epsilon 4 allele (APOE* epsilon 4). The clinical value of this information to estimate a healthy individual's lifetime risk of AD has not been well delineated. Physicians dealing with AD may not know either the lifetime risk of developing AD or the effect of the APOE genotype on this risk. Because the lifetime risk of AD depends in part on life expectancy, and available figures on APOE are not population based, a computation is necessary to derive risk estimates useful to physicians. OBJECTIVES: To estimate the lifetime risk of AD and the effect of APOE genotype information on that risk and to assess the knowledge of these risks among physicians who manage patients with dementia. DESIGN: Estimation of risk of AD and survey of physician awareness. The lifetime risk of developing AD without APOE genotype information was first computed for 65-year-olds from existing epidemiologic studies of age-related AD incidence and an actuarial life-table analysis. Using this computed a priori risk of AD and published studies of APOE genotypes in individuals with and without AD, we used a Bayesian analysis to determine the risk of developing AD, with and without an APOE* epsilon 4 allele, for unaffected 65-year-olds. To assess physician knowledge of the lifetime risk of AD and the effect of APOE genotyping on the risk, 50 neurologists, internists, geriatricians, geriatric psychiatrists, and family physicians who manage patients with dementia were randomly selected to participate in a questionnaire-driven telephone survey. RESULTS: In a person with no family history of AD, the epidemiologic/actuarial lifetime risk of AD is approximately 15%. Based on a Bayesian calculation and published APOE data, the lifetime risk of AD is 29% for individuals with one APOE* epsilon 4 allele and it is 9% if no APOE* epsilon 4 allele is present. Physician awareness survey results were as follows: 42% of physicians correctly estimated the approximate lifetime risk of AD; of these, only one third were moderately sure of their response. Only three physicians correctly estimated the change in risk given the APOE* epsilon 4 genotype; only one of these was at least moderately sure. CONCLUSIONS: Determining the APOE* epsilon 4 status of healthy adults with no family history of AD approximately doubles (for the epsilon 4 allele) or reduces by 40% (for the non-epsilon 4 allele) the uninformed lifetime risk of developing AD. Even with an APOE* epsilon 4 allele, the lifetime risk remains below 30%. Most physicians managing patients with AD do not know the lifetime risk of AD, and very few know how APOE* epsilon 4 status modifies the risk. These clinically relevant risk figures should be more widely disseminated among physicians.