APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts

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-...

Polygenic hazard scores in preclinical Alzheimer disease

“…Congruent with recent findings that the risk of dementia among APOE ε4/4 is lower than previously estimated 17 , among CNs with moderate to high amyloid load, we found that APOE did not predict clinical decline and PHS predicted change in CDR-SB even among APOE ε4 non-carriers. Our combined findings suggest that beyond APOE , PHS may prove useful both as a risk stratification and enrichment marker to identify asymptomatic individuals most likely to develop Alzheimer’s neurodegeneration.…”

Alzheimer's Prevention Initiative Generation Program: Development of an APOE genetic counseling and disclosure process in the context of clinical trials

“…To ensure consistency of communication of information to participants before and during the APOE counseling and disclosure session, the GTCD committee developed educational and session materials (e.g., Education Predisclosure Video, Genetic Counseling and Disclosure Session Handout, Genetic Counseling and Disclosure Session Talking Points) to direct the API Genetic Counseling and Disclosure Process and support providers of genetic counseling and disclosure, especially those with limited experience in delivering APOE results. To provide applicable estimates of APOE ‐associated risk of developing MCI or dementia because of AD for use in the API Genetic Counseling and Disclosure Process materials, updated lifetime risk estimates tailored to the Generation Program study population were calculated based on four large longitudinal studies [28].…”

“…To provide estimates of risk for development of mild cognitive impairment (MCI) or dementia due to AD tailored to the Generation Program study population, data from four large prospective longitudinal studies were analyzed for the incidence of MCI or dementia among initially cognitively unimpaired individuals aged 60–75 stratified by APOE genotype. The results from these analyses were published previously [28]. In brief, 5‐year risk estimates by age group (e.g., 60–64, 65–69) were found to be highly variable in comparison to lifetime risk estimates (defined as through age 85); therefore, the API Genetic Counseling and Disclosure Process provides lifetime risk estimates in the corresponding APOE genetic counseling and disclosure materials [28].…”

Alzheimer's disease progression and risk factors: A standardized comparison between six large data sets

“…Qian et al. [10] have previously identified differences in odds ratios and cumulative incidence rates between studies through meta‐analyses. However, the study could only estimate lifetime incidence for individuals that had a maximum age within the 80–85 years age band and only for two data sets.…”

“…Furthermore, a study by Qian et al. [10] which compared risk estimates for the incidence of MCI or dementia among cognitively unimpaired individuals stratified by APOE ε4 and age found that, while the effect of age and APOE ε4 was consistent between studies, there were differences in the cumulative incidence of AD between the data sets.…”