title: Age-dependent effects of APOE ε4 in preclinical Alzheimer's disease.
abstract: OBJECTIVE
  The ε4 allele of apolipoprotein E (APOE) is the strongest known common genetic risk factor for Alzheimer's disease (AD) and alters age of onset in retrospective studies. Here, we longitudinally test the effects of APOE ε4 genotype and age during progression from normal cognition to AD.
  
  
  METHODS
  Using data from 5381 cognitively normal older individuals and Cox proportional hazards models, we longitudinally tested the effects of APOE genotype on progression from normal cognition to mild cognitive impairment (MCI) or AD in four age strata (<60, 60-70, 70-80, 80 + ) and with a sliding window approach between ages 60 and 85.
  
  
  RESULTS
  We found that APOE ε4 carrier status and dosage significantly influenced progression to MCI or AD in all four age groups and that APOE ε4-associated progression risk peaked between ages 70 and 75. We confirmed APOE ε4-associated progression risk in a subset of the cohort with pathologically proven diagnoses.
  
  
  CONCLUSIONS
  Our findings indicate that in clinically normal individuals, APOE ε4 status significantly predicts progression to MCI or AD across older adulthood and that this risk varies with age. This information will be useful as therapeutic interventions become available and clinical decisions can be individually tailored based on age and genetic data.
authors.affiliation: Memory and Aging Center Department of Neurology University of California, San Francisco San Francisco California.
authors.forename: Luke W
authors.initials: LW
authors.lastname: Bonham
authors.affiliation: Memory and Aging Center Department of Neurology University of California, San Francisco San Francisco California.
authors.forename: Ethan G
authors.initials: EG
authors.lastname: Geier
authors.affiliation: Departments of Cognitive Sciences and Neurosciences University of California, San Diego La Jolla California.
authors.forename: Chun C
authors.initials: CC
authors.lastname: Fan
authors.affiliation: Department of Psychology Stanford University Palo Alto California.
authors.forename: Josiah K
authors.initials: JK
authors.lastname: Leong
authors.affiliation: National Alzheimer's Coordinating Center Department of Epidemiology University of Washington Seattle Washington.
authors.forename: Lilah
authors.initials: L
authors.lastname: Besser
authors.affiliation: National Alzheimer's Coordinating Center Department of Epidemiology University of Washington Seattle Washington.
authors.forename: Walter A
authors.initials: WA
authors.lastname: Kukull
authors.affiliation: Department of Epidemiology and Biostatistics University of California, San Francisco San Francisco California.
authors.forename: John
authors.initials: J
authors.lastname: Kornak
authors.affiliation: NORMENT Institute of Clinical Medicine University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital Oslo Norway.
authors.forename: Ole A
authors.initials: OA
authors.lastname: Andreassen
authors.affiliation: Department of Pathology and Laboratory Medicine University of Pennsylvania Perelman School of Medicine Philadelphia Pennsylvania.
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.affiliation: Memory and Aging Center Department of Neurology University of California, San Francisco San Francisco California.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Rosen
authors.affiliation: Neuroradiology Section Department of Radiology and Biomedical Imaging University of California, San Francisco San Francisco California.
authors.forename: William P
authors.initials: WP
authors.lastname: Dillon
authors.affiliation: Neuroradiology Section Department of Radiology and Biomedical Imaging University of California, San Francisco San Francisco California.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Hess
authors.affiliation: Memory and Aging Center Department of Neurology University of California, San Francisco San Francisco California.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: Departments of Cognitive Sciences and Neurosciences University of California, San Diego La Jolla California.
authors.forename: Anders M
authors.initials: AM
authors.lastname: Dale
authors.affiliation: Neuroradiology Section Department of Radiology and Biomedical Imaging University of California, San Francisco San Francisco California.
authors.forename: Rahul S
authors.initials: RS
authors.lastname: Desikan
authors.affiliation: Memory and Aging Center Department of Neurology University of California, San Francisco San Francisco California.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Yokoyama