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Ann Clin Transl Neurol. 2016 Aug 26;3(9):668-77. doi: 10.1002/acn3.333. eCollection 2016 Sep.

Age-dependent effects of APOE ε4 in preclinical Alzheimer's disease.

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Memory and Aging Center Department of Neurology University of California, San Francisco San Francisco California.
Departments of Cognitive Sciences and Neurosciences University of California, San Diego La Jolla California.
Department of Psychology Stanford University Palo Alto California.
National Alzheimer's Coordinating Center Department of Epidemiology University of Washington Seattle Washington.
Department of Epidemiology and Biostatistics University of California, San Francisco San Francisco California.
NORMENT Institute of Clinical Medicine University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital Oslo Norway.
Department of Pathology and Laboratory Medicine University of Pennsylvania Perelman School of Medicine Philadelphia Pennsylvania.
Neuroradiology Section Department of Radiology and Biomedical Imaging University of California, San Francisco San Francisco California.



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.


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.


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.


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.

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