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

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

Andrew S P Lim  1 , Lei Yu, Matthew Kowgier, Julie A Schneider, Aron S Buchman, David A Bennett
Affiliations

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

Andrew S P Lim et al. JAMA Neurol. 2013 Dec.

Abstract

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.

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Conflict of interest statement

Conflicts of Interest and Disclosures:

Dr. Lim reports no relevant conflicts of interest for this manuscript. He has served as a consultant for UCB Pharma Inc and Merck & Co. Inc. He receives research funding from the CIHR. Dr. Yu reports no relevant conflicts of interest for this manuscript. Dr. Kowgier reports no relevant conflicts of interest for this manuscript. Dr. Schneider reports no relevant conflicts of interest for this manuscript. Dr. Schneider has received consulting fees or sat on paid advisory boards for AVID radiopharmaceuticals, Eli Lilly Inc., and GE Healthcare. She is a monitoring editor of the Journal of Histochemistry and Cytochemistry and on the editorial board of International Journal of Clinical and Experimental Pathology. Dr. Schneider receives research funding from the NIH. Dr. Buchman reports no relevant conflicts of interest for this manuscript. He receives research support from the NIH. Dr. Bennett reports no relevant conflicts of interest for this manuscript. He serves on the editorial board of Neurology, Neuroepidemiology, and Current Alzheimer’s Research; has received honoraria for non-industry sponsored lectures; has served as a consultant to Nutricai, Inc., Eli Lilly, Inc., Enymotic, Ltd., Gerson Lehrman Group; and receives research support from the NIH and the Illinois Department of Public Health.

Figures

Figure 1
Figure 1. APOE Genotype, Sleep Consolidation, Cumulative Incidence of AD and Rate of Cognitive Decline
The model predicted cumulative incidence of AD and rate of cognitive decline based on the entire cohort are illustrated for hypothetical average APOE ε4+ and ε4− participants with poor (A,D 10th percentile), median (B,E 50th percentile), and good (C,F 90th percentile) sleep consolidation (kRA = 0.037, 0.027 and 0.021).
Figure 2
Figure 2. APOE Genotype, Sleep Consolidation, AD Pathology, and Cognitive Function Proximate to Death
The model predicted composite global cognitive function proximate to death (A), Aβ pathology at autopsy (B) and neurofibrillary tangle density at autopsy (C) based on deceased participants are illustrated for hypothetical average APOE ε4+ and ε4− participants with poor (10th percentile), median (50th percentile), and good (90th percentile) sleep consolidation. Vertical bars indicate 95% confidence intervals.
See this image and copyright information in PMC

Comment in

References

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