Modification of the relationship of the apolipoprotein E ε4 allele to the risk of Alzheimer disease and neurofibrillary tangle density by sleep

JAMA Neurol. 2013 Dec;70(12):1544-51. doi: 10.1001/jamaneurol.2013.4215.


Importance: The apolipoprotein E (APOE [GenBank, 348; OMIM, 107741]) ε4 allele is a common and well-established genetic risk factor for Alzheimer disease (AD). Sleep consolidation is also associated with AD risk, and previous work suggests that APOE genotype and sleep may interact to influence cognitive function.

Objective: To determine whether better sleep consolidation attenuates the relationship of the APOE genotype to the risk of incident AD and the burden of AD pathology.

Design, setting, and participants: A prospective longitudinal cohort study with up to 6 years of follow-up was conducted. Participants included 698 community-dwelling older adults without dementia (mean age, 81.7 years; 77% women) in the Rush Memory and Aging Project.

Exposures: We used up to 10 days of actigraphic recording to quantify the degree of sleep consolidation and ascertained APOE genotype.

Main outcomes and measures: Participants underwent annual evaluation for AD during a follow-up period of up to 6 years. Autopsies were performed on 201 participants who died, and β-amyloid (Aβ) and neurofibrillary tangles were identified by immunohistochemistry and quantified.

Results: During the follow-up period, 98 individuals developed AD. In a series of Cox proportional hazards regression models, better sleep consolidation attenuated the effect of the ε4 allele on the risk of incident AD (hazard ratio, 0.67; 95% CI, 0.46-0.97; P = .04 per allele per 1-SD increase in sleep consolidation). In a series of linear mixed-effect models, better sleep consolidation also attenuated the effect of the ε4 allele on the annual rate of cognitive decline. In individuals who died, better sleep consolidation attenuated the effect of the ε4 allele on neurofibrillary tangle density (interaction estimate, -0.42; SE = 0.17; P = .02), which accounted for the effect of sleep consolidation on the association between APOE genotype and cognition proximate to death.

Conclusions and relevance: Better sleep consolidation attenuates the effect of APOE genotype on incident AD and development of neurofibrillary tangle pathology. Assessment of sleep consolidation may identify APOE+ individuals at high risk for incident AD, and interventions to enhance sleep consolidation should be studied as potentially useful means to reduce the risk of AD and development of neurofibrillary tangles in APOE ε4+ individuals.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actigraphy
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease* / epidemiology
  • Alzheimer Disease* / genetics
  • Alzheimer Disease* / pathology
  • Amyloid beta-Peptides / metabolism
  • Apolipoprotein E4 / genetics*
  • Cognition Disorders / diagnosis
  • Cognition Disorders / epidemiology
  • Cognition Disorders / genetics
  • Cohort Studies
  • Dementia / diagnosis
  • Female
  • Genotype
  • Humans
  • Male
  • Neurofibrillary Tangles / genetics*
  • Neurofibrillary Tangles / pathology
  • Neuropsychological Tests
  • Sleep / genetics*


  • Amyloid beta-Peptides
  • Apolipoprotein E4