AAIC Press Release
Sleep Duration, Sleep Disorders, and Circadian Patterns are Risk Factors and Indicators of Cognitive Decline
VANCOUVER, July 16, 2012 – Four studies reported today at the Alzheimer's Association International Conference® 2012 (AAIC® 2012) in Vancouver suggest a relationship between sleep quality and quantity and risk of cognitive decline, and that interventions to normalize sleep duration and correct sleep disorders may not only improve quality of life, but have potential to reduce or prevent cognitive decline.
"We know that sleep patterns change as people age and that poor sleep affects overall health. What we don't know for certain is whether poor sleep has long-term consequences on cognitive function," said William Thies, PhD, Alzheimer's Association® chief medical and scientific officer.
"The studies presented today at AAIC suggest that cognitive health declines over the long term in some people with sleep problems. The good news is that tools already exist to monitor sleep duration and quality and to intervene to help return sleep patterns to normal. If we do this, there is the possibility that we may also help people preserve their cognitive health, but that needs to be tested," Thies added.
Too little and too much sleep are associated with lower cognition
Growing evidence suggests that sleep duration that is shorter or longer than the recommended seven hours per day may increase risk of cardiovascular disease and type 2 diabetes. However, little research has been conducted examining whether sleep duration influences cognition among older individuals.
Elizabeth Devore, ScD, of Brigham and Women's Hospital, Boston, and colleagues examined data for more than 15,000 participants in the Nurses' Health Study. All were age 70 or older at their first cognitive examination between 1995 and 2000. Follow-up cognitive assessments were conducted every other year for six years. Participants' daily sleep duration was categorized as ≤5, 6, 7, 8 or ≥9 hours (7 hours per day was considered normal). Average sleep duration was self-reported in 1986 (when women were ages 40 to 65) and 2000 (when women were ages 54 to 79).
The scientists found that:
- Participants who slept 5 hours per day or less had lower average cognition than those who slept 7 hours per day.
- Those who slept 9 hours per day or more also had lower average cognition than those who slept 7 hours per day.
- Too little or too much sleep was cognitively equivalent to aging by 2 years.
When the researchers evaluated the effects of change in sleep duration from mid- to later- life, they observed that women whose sleep changed by 2 hours per day or more had worse cognitive function than those with no change in sleep duration, independent of their initial sleep duration.
To explore sleep duration in relation to an early biomarker of Alzheimer's, the scientists examined the association with plasma levels of a ratio of proteins indicative of Alzheimer's disease brain changes (beta amyloid 42/40 ratio), which was measured in a small subset of women who provided blood samples in 1999-2000. They found that sleep durations of more than 7 or less than 7 hours per day were associated with declining ratios of Aβ42/40 compared to sleep durations of 7 hours per day.
"Our findings support the notion that extreme sleep durations and changes in sleep duration over time may contribute to cognitive decline and early Alzheimer's changes in older adults," Devore said. "The public health implications of these findings could be substantial, as they might lead to the eventual identification of sleep- and circadian- based strategies for reducing risk of cognitive impairment and Alzheimer's."
Sleep disorders, circadian disruptions associated with increased risk of cognitive impairment
As people age, they are more likely to develop problems with sleeping, such as insomnia, sleep apnea and disruptions in circadian rhythm. (Circadian rhythms are physical, mental and behavioral changes that follow a 24-hour cycle.) Whether these problems affect one's cognitive function or risk of developing mild cognitive impairment (MCI) or dementia is not definitively known.
"Studies that have explored the relationship between sleep and dementia are often cross sectional and depend on the participant's self-report rather than objective measures of sleep quality," said Kristine Yaffe, MD, of the University of California, San Francisco.
Instead, Yaffe and colleagues conducted a series of studies evaluating more than 1,300 older women (≥75) enrolled in a large multi-center study to investigate the relationship between objectively measured sleep quality (using actigraphy* and polysomnography**) and adverse cognitive outcomes.
* Actigraphy is a method of monitoring rest/activity cycles. A small sensor unit is worn, usually on the wrist, to measure gross motor activity. The unit continually records the movements it undergoes.
** Polysomnography, also known as a sleep study, is a comprehensive recording of the physical changes that occur during sleep. The PSG monitors many body functions including brain, eye movements, muscle activity or skeletal muscle activation, breathing functions, and heart rhythm.
Over five years, the researchers assessed cognitive function and clinical cognitive status (normal, MCI or dementia) and obtained objective measures of sleep parameters, including sleep apnea, nighttime wakefulness, total sleep time, and shifts in circadian rhythm.
The scientists found that:
- Participants with sleep-disordered breathing or sleep apnea had more than twice the odds of developing MCI or dementia over the five years compared with those who did not have sleep-disordered breathing.
- Women who developed a disruption of their circadian rhythm (delay in the acrophase) over the five years were at increased risk of developing MCI or dementia compared with individuals who did not.
- Participants with greater nighttime wakefulness were more likely to score worse on tests of global cognition and verbal fluency than those without it.
"We believe that these results indicate that the relationship between sleep disordered breathing and dementia may be connected to the decrease in oxygen associated with sleep apnea and not to disrupted patterns of sleep," Yaffe said.
"Overall, our findings support a relationship between sleep disturbances and cognitive decline in late age. They suggest that health practitioners should consider assessing older people with sleep disorders for changes in cognition," Yaffe said. "In addition, with additional long-term research, treatment of sleep disorders may be a promising method of delaying the development of MCI and dementia."
Sleep complaints and risk of cognitive decline in the elderly
Sleep quality and quantity often decrease as people age, but whether this is associated with risk of cognitive decline is a subject of ongoing investigation.
To better understand the potential relationship between sleep and cognitive decline, Dr. Claudine Berr of INSERM, Montpellier, France, and colleagues examined data from the French Three-City Study, an ongoing, long-term, multisite study of the relationship between vascular disease and dementia in community-dwelling individuals age 65 or older. Cognitive data were obtained at baseline and at 2, 4, and 8 years' follow-up; an ancillary project gathered data on sleep complaints at baseline.
Researchers analyzed data from 4,894 nondemented study participants who had completed sleep questionnaires, had Mini Mental State Examination (MMSE) scores of ≥24 at baseline, and for whom data from at least one follow-up evaluation was available. Cognitive decline was defined as a decrease of four or more points on the MMSE at the three follow-up points. Researchers analyzed data for each of the five subcomponents of insomnia: (1) poor sleep quality, (2) difficulty initiating sleep, (3) difficulty maintaining sleep, and (4) early morning awakening; and excessive daytime sleepiness.
They found that excessive daytime sleepiness, which was reported by 17.9 percent of participants, independently increased risk of cognitive decline. In contrast, difficulty maintaining sleep, reported by 63.5 percent of participants, was negatively associated with risk of cognitive decline.
"These results suggest that excessive daytime sleepiness may be an early predictor of cognitive decline and that sleep complaints should be adequately evaluated in older persons," said the study's researchers.
Abnormal circadian patterns found in people with dementia
The amyloid hypothesis of Alzheimer's suggests that increased production or decreased clearance of amyloid-beta (Aβ) protein ultimately culminates in Alzheimer's disease. Changes in detectable amyloid proteins ion the body, such as decreased cerebrospinal fluid (CSF) Aβ42, have been recognized as biomarkers for the disease. However, the dynamics of Aβ concentrations over time are not well understood.
The amyloid hypothesis of Alzheimer's suggests that increased production or decreased clearance of amyloid-beta 42 (Aβ42) protein ultimately contributes to Alzheimer's disease. Changes in detectable amyloid proteins in the body, such as decreased cerebrospinal fluid (CSF) Aβ42, have been recognized as biomarkers for the disease. However, the dynamics of Aβ concentrations over time, and changes in these proteins over the course of a 24-hour day, are not well understood. These dynamic changes are important to understand because CSF biological markers that could represent early Alzheimer's-like changes in people not yet showing Alzheimer's dementia symptoms will need to be measured consistently and accurately. The time of day of measurement and changes with age are critical to this standardized accurate measurement.
Supporting the above-mentioned initial data, a study at Washington University School of Medicine, St. Louis, Missouri, including people with dementia, age-matched participants, and younger participants, found circadian patterns in CSF and plasma amyloid beta, and CSF amyloid precursor protein, all of which are associated with Alzheimer's disease.
Yafei Huang MD, PhD and colleagues obtained hourly CSF and plasma samples over a 36-hour study period in all three groups. They investigated dynamic patterns of key Alzheimer's-associated Aβ variants (Aβ40 and Aβ42) in CSF and plasma, and amyloid precursor protein (APP). They then analyzed the effects of amyloidosis on circadian patterns, aging and correlations between CSF and plasma Aβ.
Circadian patterns which were reflected in protein level changes over the course of a 36-hour period were observed in CSF and plasma Aβ. CSF APP also demonstrated a circadian pattern. In addition, CSF APP-α, APP-β, Aβ40, and Aβ42 were highly positively correlated in all participants without amyloidosis. However, in participants with amyloidosis, there is no correlation of Aβ42 to the other APP metabolites, suggesting that normal physiologic regulation of CSF Aβ42 is impaired in the presence of amyloidosis.
"Our study suggests amyloid proteins are dynamic and regulated in a circadian pattern that is part of the normal control of Aβ concentrations. Regulatory mechanisms of these proteins may be altered with aging and amyloidosis," said Huang. "These findings support the idea of an active circadian regulation of beta-amyloid and may provide insight into the pathophysiological changes of Alzheimer's."
"These findings indicate that circadian rhythms and age should be studied further and better understood as research in CSF biological markers moves forward to ensure standardized, accurate measurements of key Alzheimer's proteins for future early detection of the disease," Thies added.
The Alzheimer's Association International Conference® (AAIC) is the world's largest conference of its kind, bringing together researchers from around the world to report and discuss groundbreaking research and information on the cause, diagnosis, treatment and prevention of Alzheimer's disease and related disorders. As a part of the Alzheimer's Association's research program, AAIC serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.
About the Alzheimer's Association®
The Alzheimer's Association is the world's leading voluntary health organization in Alzheimer's care, support and research. Our mission is to eliminate Alzheimer's through the advancement of research, to provide and enhance care and support for all affected, and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's. Visit www.alz.org or call 800-272-3900.
- Elizabeth Devore, et al. Sleep Duration and Cognitive Function: The Nurses' Health Study.
- Kristine Yaffe, et al. Sleep Disorders and Cognitive Function in Older Women. (Funder: National Insitiute on Aging)
- Claudine Berr, et al. Sleep and Cognitive Decline in the Elderly: The French Three-City Cohort. (Funders: The 3C Study is conducted under a partnership agreement between Inserm, the Victor Segalen – Bordeaux II University and Sanofi-Synthélabo. Also: The Fondation pour la Recherche Médicale, Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Regional Governments of Aquitaine, Bourgogne and Languedoc-Roussillon and, the Fondation de France, the Ministry of Research-Inserm Programme "Cohorts and collection of biological material," Eisai, Agence Nationale de la Recherche, Fonds de Coopération Scientifique Alzheimer.)
- Yafei Huang, et al. Circadian Patterns of Beta-Amyloid in Human CSF and Plasma. (Funders: AstraZeneca, National Institutes of Health, Knight Initiative for Alzheimer Research)
F2-03-01 Monday, July 16 / AAIC 2012 Featured Research Session, 8:30–10 a.m.
Sleep Duration and Cognitive Function: The Nurses' Health Study
Elizabeth Devore1, Francine Grodstein2, Eva Schernhammer3
1UCSF, San Francisco, California, United States; 2Harvard School of Public Health, Boston, Massachusetts, United States; 3 Brigham & Women's Hospital, Boston, Massachusetts, United States
Presenting author e-mail: email@example.com
Background: Growing evidence suggests that shorter or longer sleep duration increases risks of cardiovascular disease and type 2 diabetes. Yet, little research has explored the association between sleep duration in older adults and cognitive status.
Methods: We evaluated 15,263 participants of the Nurses' Health Study, ≥70 years of age at initial cognitive assessment in 1995-2000. Three follow-up cognitive assessments were given biennially. Near cognitive baseline, women reported average sleep duration. In addition, a small subset of women (n=468) had plasma amyloid beta (Aβ) measured at baseline; we examined the ratio of Aβ42/40, which predicts cognitive decline and dementia in prospective studies. We used multivariable-adjusted linear regression to estimate mean differences in overall cognitive status at older age (the average of all four repeated measures) as well as mean difference in Aβ42/40, and multivariable-adjusted mixed linear regression models to estimate mean differences in slopes of cognitive decline, across categories of sleep duration (≤5, 6, 7, 8, ≥9 hours/day).
Results: There was an inverse U-shaped association between sleep duration and overall cognition (the average of all 4 repeated measures) in multivariable-adjusted models for a global cognitive score, combining the six cognitive tests in our battery (p<0.0001 for quadratic term). For example, women whose sleep duration was ≤5 hours/day had lower average cognition compared to those with sleep duration of 7 hours/day (e.g., mean difference=-0.07 standard units [95% CI: -0.11, -0.03]). Similarly, women who reported sleep durations of ≥9 hours/day demonstrated worse average cognition compared to 7 hours (e.g., for global score, mean difference=-0.10 standard units [95% CI: -0.13, -0.06]). These effect estimates were similar to those we find for approximately 2 years of age; that is, having abnormal sleep duration was cognitively equivalent to aging by two years. Furthermore, sleep durations of >7 or <7 hours/day were associated with lower ratios of Aβ42/40 compared to 7 hours, potentially indicating disproportionate accrual of soluble Aβ-42 into insoluble plaques in the brain. There was no clear relation of sleep duration to change in cognitive function.
Conclusions: Sleep durations that were shorter or longer than normal were associated with worse cognition in later life, consistent with findings for other chronic diseases.
F2-03-02 Monday, July 16 / AAIC 2012 Featured Research Session, 8:30–10 a.m.
Sleep Disorders and Cognitive Function in Older Women
Kristine Yaffe1, Adam Spira2, Greg Tranah3, Katie Stone3
1University of California, San Francisco, San Francisco, California, United States,1Harvard School of Public Health, Boston, Massachusetts, United States; 2Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States; 3California Pacific Medical Center, San Francisco, California
Presenting author e-mail: firstname.lastname@example.org
Background: Sleep disorders including insomnia, sleep apnea and circadian rhytym disruption are common among older adults. We prospectively examined the association between objectively measured sleep disorders and subsequent cognitive function and diagnosis of mild cognitive impairment (MCI) or dementia.
Methods: We studied 1309 women (mean age, 82.3 ± 3.2) who were enrolled in an ongoing prospective study and completed several days of wrist actigraphy and a subset (N=298) with overnight polysomnography (PSG). Approximately 5 years later, we assessed cognitive outcomes including a neuropsychological test battery and adjudicated clinical cognitive status (normal, MCI or dementia). Sleep parameters of interest included: apnea-hypopnea index (AHI) score ≥ 15 events/hr to define sleep disordered breathing (SDB); sleep fragmentation, as manifested by greater nighttime wakefulness after onset (WASO); total sleep time (TST); and circadian rhythm acrophase shift.
Results: Women with SDB had more than twice the odds of developing MCI/dementia (adjusted odds ratio [OR] = 2.33, 95% confidence interval [CI] 1.28 - 4.25) compared to women without SDB. Increased risk of MCI/dementia (adjusted OR=1.71, 95% CI, 1.22-2.45) was also observed for women with a delayed acrophase (>1 SD from mean) when compared to those with average acrophase timing. Women with greater nighttime wakefulness had greater likelihood of impaired performance on a test of global cognition (adjusted OR = 2.37, 95% CI 1.16- 4.87), verbal fluency (adjusted OR = 2.17, 95% CI 1.10- 4.28) and delayed verbal recall (adjusted OR = 1.83, 95% CI 0.94,-3.54). TST was not associated with cognitive impairment.
Conclusions: Sleep disturbances are associated with increased risk of developing cognitive impairment 5-years later in older women. These findings suggest that older adults should be monitored for sleep disturbances and that interventions designed to improve sleep need to be investigated with particular attention to cognitive outcomes.
F2-03-03 Monday, July 16 / AAIC 2012 Featured Research Session, 8:30–10 a.m.
Sleep and Cognitive Decline in the Elderly: The French Three-City Cohort
Claudine Berr1, Isabelle Jaussent1, Jean Bouyer1, Marie-Laure Ancelin1, Alexandra FOUBERT-SAMIER1, Karen Ritchie1, Maurice M Ohayon2, Alain Besset1, Yves Dauvilliers1
1INSERM, Montpellier, France; 2Stanford University, Stanford, California, United States
Presenting author e-mail: email@example.com
Background: As sleep decreases physiologically in quantity and quality with age, insomnia and excessive daytime sleepiness (EDS) are frequently reported in the elderly. Relationships between sleep and cognitive decline still remain controversial. In the frame of a large population-based study, we examined the association between different insomnia subcomponents reported at baseline and cognitive decline.
Methods: The French Three-City Study is an ongoing multisite longitudinal study whose main goal is to examine the relation between vascular diseases and dementia in subjects aged 65 and older living in the community. Cognitive performance (including MMSE score), clinical diagnosis of dementia (validated by an independent panel of neurologists), and medication use were evaluated at baseline, and 2, 4, and 8 year follow-up. In an ancillary project, sleep complaints were assessed at baseline by a face-to-face standardized interview with a sleep questionnaire. We analyzed data on 4894 non-demented subjects: 1) with complete sleep questionnaires; 2) having a Mini Mental Status Examination (MMSE) score ≥ 24 points at baseline; 3) with at least one follow up and no missing covariate data. Incident cognitive decline was defined as a 4-point reduction in MMSE score during follow-up. Logistic regression models were adjusted for sociodemographic, behavioral, physical and mental health variables, prescribed sleep medication and APOE genotype
Results: EDS, reported by 17.9% of subjects, independently increased the risk of cognitive decline (OR=1.26, 95% CI=1.02-1.56) while difficulty in maintaining sleep (63.5% of subjects) was negatively associated (OR=0.81 95% CI=0.68-0.96, respectively). The three others components of insomnia (poor sleep quality, 12.4%; difficulty in initiating sleep, 33.8%; early morning awakening, 35.7%) were not significantly associated with decline on the MMSE.
Conclusions: Our results show that EDS may be associated independently with the risk of cognitive decline in the elderly population. These results suggest that EDS may be considered as an early unspecific neurological predictor of incident cognitive decline and that sleep complaint should be adequately evaluated in older persons.
F2-03-04 Monday, July 16 / AAIC 2012 Featured Research Session, 8:30–10 a.m.
Circadian Patterns of Beta-Amyloid in Human CSF and Plasma
Yafei Huang, Randall Bateman
Washington University School of Medicine, St. Louis, Missouri, United States
Presenting author e-mail: firstname.lastname@example.org
Background: The amyloid hypothesis predicts that increased production or decreased clearance of amyloid-beta (Aβ) leads to amyloidosis, which ultimately culminates in Alzheimer's disease (AD). Changes in amyloid proteins, such as decreased cerebrospinal fluid (CSF) Aβ42 have been recognized as a biomarker for AD. However, the dynamics of Aβ concentrations over time are not well understood.
Methods: Hourly CSF and plasma samples were obtained over a 36-hour study period in three groups of human volunteers: a dementia group with amyloid deposition, an age-matched control group, and a younger control group. We investigated dynamic patterns of Aβ peptides (Aβ40 and Aβ42 in CSF and plasma using bead-based Luminex XMAP assays), and Amyloid Precursor Protein (APP) (APP-α [please confirm that α is correct] and APP-β in CSF using ELISA assays). We then analyzed the effects of aging and amyloidosis on circadian patterns and correlations between CSF and plasma Aβ peptides.
Results: Circadian patterns were observed in CSF and plasma Aβ, with decreased amplitudes with aging. Further, CSF APP also demonstrated a circadian pattern. No significant correlations were found between plasma and CSF Aβ levels on an hourly or individual basis. We also found that CSF APP-α, [please confirm that α is correct] APP-β, Aβ40, and Aβ42 are highly positively correlated in all participants without amyloidosis. However, in participants with amyloidosis, there is no correlation of Aβ42 to the other APP metabolites, suggesting that normal physiologic regulation of CSF Aβ42 is impaired in the presence of amyloidosis.
Conclusions: This study suggests amyloid proteins in both central and peripheral compartments are dynamic, and regulated in a circadian pattern that is part of the normal dynamic physiologic control of Aβ concentrations. Regulatory mechanisms of these proteins may be altered with aging and amyloidosis. The lack of correlation of plasma and CSF Aβ levels suggest plasma Aβ concentrations can not be used for surrogates of central Aβ concentrations. These findings support an active circadian regulation of Aβ and may provide insight into the pathophysiological changes in AD.
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