Date Published: March 21, 2017
Publisher: Public Library of Science
Author(s): Jing Qian, Frank J. Wolters, Alexa Beiser, Mary Haan, M. Arfan Ikram, Jason Karlawish, Jessica B. Langbaum, John M. Neuhaus, Eric M. Reiman, J. Scott Roberts, Sudha Seshadri, Pierre N. Tariot, Beth McCarty Woods, Rebecca A. Betensky, Deborah Blacker, Bruce L. Miller
Abstract: BackgroundWith the onset of prevention trials for individuals at high risk for Alzheimer disease, there is increasing need for accurate risk prediction to inform study design and enrollment, but available risk estimates are limited. We developed risk estimates for the incidence of mild cognitive impairment (MCI) or dementia among cognitively unimpaired individuals by APOE-e4 dose for the genetic disclosure process of the Alzheimer’s Prevention Initiative Generation Study, a prevention trial in cognitively unimpaired APOE-e4/e4 homozygote individuals.Methods and findingsWe included cognitively unimpaired individuals aged 60–75 y, consistent with Generation Study eligibility criteria, from the National Alzheimer’s Coordinating Center (NACC) (n = 5,073, 158 APOE-e4/e4), the Rotterdam Study (n = 6,399, 156 APOE-e4/e4), the Framingham Heart Study (n = 4,078, 67 APOE-e4/e4), and the Sacramento Area Latino Study on Aging (SALSA) (n = 1,294, 11 APOE-e4/e4). We computed stratified cumulative incidence curves by age (60–64, 65–69, 70–75 y) and APOE-e4 dose, adjusting for the competing risk of mortality, and determined risk of MCI and/or dementia by genotype and baseline age. We also used subdistribution hazard regression to model relative hazard based on age, APOE genotype, sex, education, family history of dementia, vascular risk, subjective memory concerns, and baseline cognitive performance. The four cohorts varied considerably in age, education, ethnicity/race, and APOE-e4 allele frequency. Overall, cumulative incidence was uniformly higher in NACC than in the population-based cohorts. Among APOE-e4/e4 individuals, 5-y cumulative incidence was as follows: in the 60–64-y age stratum, it ranged from 0% to 5.88% in the three population-based cohorts versus 23.06% in NACC; in the 65–69-y age stratum, from 9.42% to 10.39% versus 34.62%; and in the 70–75-y age stratum, from 18.64% to 33.33% versus 38.34%. Five-year incidence of dementia was negligible except for APOE-e4/e4 individuals and those over 70 y. Lifetime incidence (to age 80–85 y) of MCI or dementia for the APOE-e4/e4 individuals in the long-term Framingham and Rotterdam cohorts was 34.69%–38.45% at age 60–64 y, 30.76%–40.26% at 65–69 y, and 33.3%–35.17% at 70–75 y. Confidence limits for these estimates are often wide, particularly for APOE-e4/e4 individuals and for the dementia outcome at 5 y. In regression models, APOE-e4 dose and age both consistently increased risk, as did lower education, subjective memory concerns, poorer baseline cognitive performance, and family history of dementia. We discuss several limitations of the study, including the small numbers of APOE-e4/e4 individuals, missing data and differential dropout, limited ethnic and racial diversity, and differences in definitions of exposure and outcome variables.ConclusionsEstimates of the absolute risk of MCI or dementia, particularly over short time intervals, are sensitive to sampling and a variety of methodological factors. Nonetheless, such estimates were fairly consistent across the population-based cohorts, and lower than those from a convenience cohort and those estimated in prior studies—with implications for informed consent and design for clinical trials targeting high-risk individuals.
Partial Text: At present, 48 million people worldwide have dementia, and this number is projected to increase to 131 million by 2050 . Consequently, prevention of Alzheimer disease, the most common cause of dementia, has become a major research focus, with several prevention trials now underway [2–7]. The feasibility of these trials will in part depend on the ability to recruit individuals at risk of developing disease during the trial period. One strategy to achieve this focuses on individuals at high genetic risk. The Alzheimer’s Prevention Initiative  is embarking on two clinical trials targeting cognitively unimpaired individuals at highest genetic risk for Alzheimer disease, one trial in an extended early-onset Columbian kindred carrying a fully penetrant presenilin 1 mutation, and the Generation Study (NCT02565511), a trial in individuals aged 60–75 y who carry two copies of the Alzheimer disease risk allele apolipoprotein E epsilon 4 (APOE-e4). The Generation Study is a double-blind, randomized, placebo-controlled clinical trial of two different anti-amyloid agents in approximately 1,300 participants. Recruitment is through several sources, notably in the United States through the GeneMatch  Alzheimer disease prevention registry (NCT02564692). High-volume recruitment efforts are required because the APOE-e4/e4 genotype occurs in approximately 1%–2% of the general population, so thousands of individuals must be screened to identify eligible participants. An assessment of absolute risk among trial-eligible individuals in a meaningful time frame is essential for the informed consent process in the trial, as well as trial design. However, although numerous studies [10–14] document that APOE-e4 increases the relative risk of Alzheimer disease (compared to no copies of APOE-e4, there is a 2- to 4-fold increase in risk for one copy of APOE-e4, and an 8-to 15-fold increase for two copies), its effect on absolute risk is less clear.