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



We 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.



Estimates 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.
Department of Biostatistics and Epidemiology, University of Massachusetts Amherst, Amherst, Massachusetts, United States of America.
Jing
0000-0001-6120-5147
J
Qian
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
Frank J
0000-0003-2226-4050
FJ
Wolters
Department of Neurology, Boston University Medical School, Boston, Massachusetts, United States of America.|Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
Alexa
0000-0001-8551-7778
A
Beiser
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, United States of America.
Mary
0000-0001-9312-4501
M
Haan
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
M Arfan
MA
Ikram
Department of Medicine, University of Pennsylvania Medical School, Philadelphia, Pennsylvania, United States of America.
Jason
J
Karlawish
Banner Alzheimer's Institute, Phoenix, Arizona, United States of America.
Jessica B
JB
Langbaum
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, United States of America.
John M
JM
Neuhaus
Banner Alzheimer's Institute, Phoenix, Arizona, United States of America.|Department of Psychiatry, University of Arizona College of Medicine, Phoenix, Arizona, United States of America.|Arizona State University-Banner Neurodegenerative Disease Research Center, Tempe, Arizona, United States of America.|Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
Eric M
EM
Reiman
Department of Health Behavior & Health Education, University of Michigan School of Public Health, Ann Arbor, Michigan, United States of America.
J Scott
JS
Roberts
Department of Neurology, Boston University Medical School, Boston, Massachusetts, United States of America.
Sudha
S
Seshadri
Banner Alzheimer's Institute, Phoenix, Arizona, United States of America.|Department of Psychiatry, University of Arizona College of Medicine, Phoenix, Arizona, United States of America.
Pierre N
PN
Tariot
Department of Medicine, University of Pennsylvania Medical School, Philadelphia, Pennsylvania, United States of America.
Beth McCarty
0000-0002-4734-2214
BM
Woods
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.
Rebecca A
RA
Betensky
Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.
Deborah
0000-0001-6107-7376
D
Blacker
D000368:Aged; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000453:epidemiology* / Q000235:genetics; D015331:Cohort Studies; D003704:Dementia / Q000453:epidemiology* / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D012307:Risk Factors; D014481:United States
C000612345:ApoE protein, human; D001057:Apolipoproteins E