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Modification of the relationship of the apolipoprotein E ?4 allele to the risk of Alzheimer disease and neurofibrillary tangle density by sleep.

ABSTRACT: The apolipoprotein E (APOE [GenBank, 348; OMIM, 107741]) ?4 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.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.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.We used up to 10 days of actigraphic recording to quantify the degree of sleep consolidation and ascertained APOE genotype.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 ?-amyloid (A?) and neurofibrillary tangles were identified by immunohistochemistry and quantified.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 ?4 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 ?4 allele on the annual rate of cognitive decline. In individuals who died, better sleep consolidation attenuated the effect of the ?4 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.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 ?4+ individuals.

SUBMITTER: Lim AS

PROVIDER: S-EPMC3859706 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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

Lim Andrew S P AS Yu Lei L Kowgier Matthew M Schneider Julie A JA Buchman Aron S AS Bennett David A DA

JAMA neurology 20131201 12

<h4>Importance</h4>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.<h4>Objective</h4>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.<h4>De ...[more]

PMID: 24145819

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Project description:ImportanceThe heterogeneity of rate of clinical progression among patients with Alzheimer disease leads to difficulty in providing clinical counseling and diminishes the power of clinical trials using disease-modifying agents.ObjectiveTo gain a better understanding of the factors that affect the natural history of progression in Alzheimer disease for the purpose of improving both clinical care and clinical trial design.Design, setting, and participantsA longitudinal cohort study of aging from 2005 to 2014 in the National Alzheimer Coordinating Center. Clinical evaluation of the participants was conducted in 31 National Institute on Aging's Alzheimer Disease Centers. Nine hundred eighty-four participants in the National Alzheimer Coordinating Center cohort study who died and underwent autopsy and met inclusion and exclusion criteria.Main outcomes and measuresWe sought to model the possibility that knowledge of neurofibrillary tangle burden in the presence of moderate or frequent plaques would add to the ability to predict clinical rate of progression during the ensuing 2 to 3 years. We examined the National Alzheimer Coordinating Center autopsy data to evaluate the effect of different neurofibrillary tangle stages on the rates of progression on several standard clinical instruments: the Clinical Dementia Rating Scale sum of boxes, a verbal memory test (logical memory), and a controlled oral word association task (vegetable naming), implementing a reverse-time longitudinal modeling approach in conjunction with latent class estimation to adjust for unmeasured sources of heterogeneity.ResultsSeveral correlations between clinical variables and neurocognitive performance suggest a basis for heterogeneity: Higher education level was associated with lower Clinical Dementia Rating Scale sum of boxes (β = -0.19; P < .001), and frequent vs moderate neuritic plaques were associated with higher Clinical Dementia Rating Scale sum of boxes (β = 1.64; P < .001) and lower logical memory score (β = -1.07; P = .005). The rate of change of the clinical and cognitive scores varied depending on Braak stage, when adjusting for plaques, age of death, sex, education, and APOE genotype. For example, comparing high vs low Braak stage with other variables fixed, the logical memory score decreased a substantial 0.38 additional units per year (95% CI, -0.70 to -0.06; P = .02). Using these data, we estimate that a 300-participant clinical trial with end point of a 20% improvement in slope in rate of change of Clinical Dementia Rating Scale sum of boxes has 89% power when all participants in the trial are from the high Braak stage, compared with 29% power if Braak stage had not used for eligibility.Conclusions and relevanceWe found that knowledge of neurofibrillary tangle stage, modeled as the sort of information that could be available from tau positron-emission tomography scans and its use to determine eligibility to a trial, could dramatically improve the power of clinical trials and equivalently reduce the required sample sizes of clinical trials.

Dataset Information

Modification of the relationship of the apolipoprotein E ?4 allele to the risk of Alzheimer disease and neurofibrillary tangle density by sleep.

Publications

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

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