Current Treatment Options in Neurology

, Volume 15, Issue 6, pp 669–676 | Cite as

Alzheimer’s Disease, Sleep Apnea, and Positive Pressure Therapy

  • Donald L. Bliwise

Opinion statement

Numerous lines of evidence converge in suggesting that sleep apnea may play a causal role in severe cognitive impairment, most likely Alzheimer’s Disease (AD) but also including vascular dementia. Until recently, most of these studies have been based on small samples of clinic patients or population-based, descriptive studies of sleep apnea and cognition. Although randomized clinical trials have been completed for treating sleep apnea in middle-aged cognitively intact patients with sleep apnea using continuous positive airway pressure (CPAP), systematic intervention studies in well-characterized AD patients are very rare and have been published from only a single research group. Results suggest some very modest improvement in selected aspects of cognition over a very limited period of time. There is, thus, a lack of conclusive evidence that treating sleep apnea in AD is likely to have a major impact on dementia, although it may benefit daytime hypersomnolence, excessive napping, and lethargy so common in many dementia patients. In addition, anecdotal evidence suggests that in some selected cases, treatment can have relatively dramatic effects. At this point in time, the best indications for pursuing treatment for sleep apnea with nasal CPAP in AD patients would be factors promoting adherence, such as presence of a caregiver/family member invested in treatment, and a realistic appraisal of what goals of intervention should be expected (eg, increasing daytime functionality by enhancing alertness) over a reasonable window of time. Speculative factors implicating a potentially causal role for sleep apnea in dementing illness would be comorbid diseases well-established to be associated with both sleep apnea and dementia (cardiovascular disease, diabetes) and presence of the Apolipoprotein-E4 genotype. None of these factors have been shown conclusively to influence CPAP efficacy in dementia, but to the extent that they lie on a putative causal pathway for sleep apnea and dementia (either as moderators or mediators of CPAP efficacy), their presence might be expected to enhance, rather than mitigate, a more favorable response in the domain of cognition.


Alzheimer’s disease Sleep apnea Positive pressure therapy Impaired cognition Clinical trials 


Compliance with Ethics Guidelines

Conflict of Interest

Donald L. Bliwise has served as a consultant for Ferring Pharmaceuticals, Morehouse School of Medicine, Vantia Therapeutics, and the New England Research Institute and has received grant support from the National Institutes of Health (NS-050595, AG-020269).

Human and Animal Rights and Informed Consent

This article does not contain any studies with animal subjects performed by the author. With regard to the author’s research cited in this paper, all procedures were followed in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2000 and 2008.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Yesavage JA, Bliwise D, Guilleminault C, et al. Preliminary communication: intellectual deficit and sleep-related respiratory disturbance in the elderly. Sleep. 1985;8:30–3.PubMedGoogle Scholar
  2. 2.
    Bliwise DL. Dementia. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine. 3rd ed. Philadelphia: Saunders; 2000. p. 1058–71.Google Scholar
  3. 3.
    Bliwise DL. Sleep in independently living and institutionalized elderly. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine. 5th ed. Philadelphia: Elsevier/Saunders; 2011. p. 1551–61.CrossRefGoogle Scholar
  4. 4.
    Bliwise DL. Is sleep apnea a cause of reversible dementia in old age (editorial)? J Am Geriatr Soc. 1996;44:1407–9.PubMedGoogle Scholar
  5. 5.
    Ancoli-Israel S, Kripke DF, Klauber MR, et al. Sleep-disordered breathing in community-dwelling elderly. Sleep. 1991;14:486–95.PubMedGoogle Scholar
  6. 6.
    Ancoli-Israel S. Epidemiology of sleep disorders. Clin Geriatr Med. 1989;5:347–62.PubMedGoogle Scholar
  7. 7.
    Ancoli-Israel S, Klauber MR, Butters N, et al. Dementia in institutionalized elderly: relation to sleep apnea. J Am Geriatr Soc. 1991;39:258–63.PubMedGoogle Scholar
  8. 8.
    Ancoli-Israel S, Klauber MR, Kripke DF, et al. Sleep apnea in female patients in a nursing home: increased risk of mortality. Chest. 1989;96:1054–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Martin JL, Mory AK, Alessi CA. Nighttime oxygen desaturation and symptoms of sleep-disordered breathing in long-stay nursing home residents. J Gerontol Med Sci. 2005;60A:104–8.CrossRefGoogle Scholar
  10. 10.
    Frohnhofen H, Roffe C. Intermittent nocturnal hypoxemia in individuals with dementia: prevalence and relationship with functional status. J Am Geriatr Soc. 2012;60:1997–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Onen SH, Dubray C, Decullier E, et al. Observation-based nocturnal sleep inventory: screening tool for sleep apnea in elderly people. J Am Geriatr Soc. 2008;56:1920–5.PubMedCrossRefGoogle Scholar
  12. 12.
    Antonelli Incalzi R, Marra C, Salvigni BL, et al. Does cognitive dysfunction conform to a distinctive pattern in obstructive sleep apnea? J Sleep Res. 2004;13:79–86.PubMedCrossRefGoogle Scholar
  13. 13.
    Roman GC. Vascular dementia prevention: a risk factor analysis. Cerebrovasc Dis. 2005;20 Suppl 2:91–100.PubMedGoogle Scholar
  14. 14.
    Cerhan JR, Folsom AR, Mortimer JA, et al. The ARIC Study Investigators. Correlates of cognitive function in middle-aged adults. Gerontology. 1998;44:95–105.PubMedCrossRefGoogle Scholar
  15. 15.
    Elias MF, Wolf PA, d’Agostino RB. Untreated blood pressure level is inversely related to cognitive functioning: the Framingham Study. Am J Epidemiol. 1993;138:353–64.PubMedGoogle Scholar
  16. 16.
    Kilander L, Nyman H, Boberg M, et al. Hypertension is related to cognitive impairment: a 20-year follow-up of 999 men. Hypertension. 1998;31:780–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Farmer ME, White LR, Abbott RD, et al. Blood pressure and cognitive performance: the Framingham study. Am J Epidemiol. 1987;126:1103–14.PubMedGoogle Scholar
  18. 18.
    Launer LJ, Masaki K, Petrovitch H, et al. The association between midlife blood pressure levels and late-life cognitive function. JAMA. 1995;274:1846–51.PubMedCrossRefGoogle Scholar
  19. 19.
    Bliwise DL, Yesavage JA, Tinklenberg J, et al. Sleep apnea in Alzheimer’s Disease. Neurobiol Aging. 1989;10(4):343–6.PubMedCrossRefGoogle Scholar
  20. 20.•
    Yamout K, Goldstein FC, Lah JJ, et al. Neurocognitive correlates of nocturnal oxygen desaturation in a memory clinic population. J Clin Exp Neuropsych. 2012;34:325–32. This study is of interest because it suggests utility of a simple pulse oximetry screening protocol easily adapted in the setting of an ambulatory memory clinic. CrossRefGoogle Scholar
  21. 21.
    Bliwise DL, Nekich JC, Dement WC. Relative validity of self-reported snoring as a symptom of sleep apnea. Chest. 1991;99:600–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Sforza E, Roche F, Thomas-Anterion C, et al. Cognitive function and sleep related breathing disorders in a healthy elderly population: the Synapse Study. Sleep. 2010;33:515–21.PubMedGoogle Scholar
  23. 23.
    Tworoger SS, Lee S, Schernhammer ES, et al. The association of self-reported sleep duration, difficulty sleeping, and snoring with cognitive function in older women. Alzheimer Dis Assoc Disord. 2006;20:41–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Quan SF, Chan CS, Dement WC, et al. The association between obstructive sleep apnea and neurocognitive performance—the Apnea Positive Pressure Long-term Efficacy Study (APPLES). Sleep. 2011;34:303–14B.PubMedGoogle Scholar
  25. 25.
    Boland LL, Shahar E, Iber C, et al. Measures of cognitive function in persons with varying degrees of sleep-disordered breathing: the Sleep Heart Health Study. J Sleep Res. 2002;11:265–72.PubMedCrossRefGoogle Scholar
  26. 26.
    Ding J, Nieto FJ, Beauchamp Jr NJ, et al. Sleep-disordered breathing and white matter disease in the brainstem in older adults. Sleep. 2004;27:474–9.PubMedGoogle Scholar
  27. 27.
    Robbins J, Redline S, Ervin A, et al. Associations of sleep-disordered breathing and cerebral changes on MRI. J Clin Sleep Med. 2005;1:159–65.PubMedGoogle Scholar
  28. 28.
    Rothman KJ. Modern epidemiology. Boston: Little, Brown and Company; 1986.Google Scholar
  29. 29.
    Kushida CA, Nichols DA, Holmes TH, et al. Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: the Apnea Positive Pressure Long-term Efficacy Study (APPLES). Sleep. 2012;35:1593–602.PubMedGoogle Scholar
  30. 30.
    Weaver TE, Mancini C, Maislin G, et al. Continuous positive airway pressure treatment of sleepy patients with milder obstructive sleep apnea: results of the CPAP Apnea Trial North American Program (CATNAP) randomized clinical trial. Am J Respir Crit Care Med. 2012;186:677–83.PubMedCrossRefGoogle Scholar
  31. 31.
    Bliwise DL, Greenaway MC. Will APPLES hit a ceiling? Comment on Quan, et al. The association between obstructive sleep apnea and neurocognitive performance—the Apnea Positive Pressure Long-term Efficacy Study (APPLES). Sleep. 2011;34:249–50.PubMedGoogle Scholar
  32. 32.
    Bliwise DL. Sleep apnea, APO-E4, and Alzheimer’s disease: 20 years and counting? J Psychosom Res. 2002;53:539–46.PubMedCrossRefGoogle Scholar
  33. 33.
    Ancoli-Israel S, Palmer BW, Cooke JR, et al. Cognitive effects of treating obstructive sleep apnea in Alzheimer’s Disease. J Am Geriatr Soc. 2008;56:2076–81.PubMedCrossRefGoogle Scholar
  34. 34.
    Ayalon L, Ancoli-Israel S, Stepnowsky C, et al. Adherence to continuous positive airway pressure treatment in patients with Alzheimer’s Disease and obstructive sleep apnea. Am J Geriatr Psychiatry. 2006;14:176–80.PubMedCrossRefGoogle Scholar
  35. 35.
    Chong MS, Ayalon L, Marler M, et al. Continuous positive airway pressure reduces subjective daytime sleepiness in patients with mild to moderate Alzheimer’s disease with sleep disordered breathing. J Am Geriatr Soc. 2006;54:777–81.PubMedCrossRefGoogle Scholar
  36. 36.
    Cooke JR, Ancoli-Israel S, Liu L, et al. Continuous positive airway pressure deepens sleep in patients with Alzheimer’s disease and obstructive sleep apnea. Sleep Med. 2009;10:1101–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Cooke JR, Ayalon L, Palmer BW, et al. Sustained use of CPAP slows deterioration of cognition, sleep and mood in patients with Alzheimer’s disease and obstructive sleep apnea: a preliminary study. J Clin Sleep Med. 2009;5:305–9.PubMedGoogle Scholar
  38. 38.•
    Nikodemova M, Finn L, Mignot E, et al. Association of sleep disordered breathing and cognitive deficit in APOE e4 carriers. Sleep. 2013; 36:873–80. This study indicates that presence of APOE e4 genotype may be an effect modifier in determining the association between sleep apnea and cognitive impairment. PubMedGoogle Scholar
  39. 39.
    Caselli RJ, Reiman EM, Hentz JG, et al. A distinctive interaction between memory and chronic daytime somnolence in asymptomatic APOE e4 homozygotes. Sleep. 2002;25:447–53.PubMedGoogle Scholar
  40. 40.
    Cosentino II F, Bosco P, Drago V, et al. The APOE e4 allele increases the risk of impaired spatial working memory in obstructive sleep apnea. Sleep Med. 2008;9:831–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Gottlieb DJ, DeStefano AL, Foley DJ, et al. APOE epsilon4 is associated with obstructive sleep apnea/hypopnea: the Sleep Heart Health Study. Neurology. 2004;63:664–8.PubMedCrossRefGoogle Scholar
  42. 42.
    O’Hara R, Schroder CM, Kraemer HC, et al. Nocturnal sleep apnea/hypopnea is associated with lower memory performance in APOE e4 carriers. Neurology. 2005;65:642–4.PubMedCrossRefGoogle Scholar
  43. 43.
    Moraes W, Poyares D, Sukys-Claudino L, et al. Donepezil improves obstructive sleep apnea in Alzheimer’s disease: a double-blind, placebo-controlled study. Chest. 2008;133:677–83.PubMedCrossRefGoogle Scholar
  44. 44.
    Sukys-Claudino L, Moraes W, Guilleminault C, et al. Beneficial effect of donepezil on obstructive sleep apnea: a double-blind, placebo-controlled clinical trial. Sleep Med. 2012;13:290–6.PubMedCrossRefGoogle Scholar
  45. 45.
    Heaton RK, Grant I, McSweeny AJ, et al. Psychological effects of continuous and nocturnal oxygen therapy in hypoxemic chronic obstructive pulmonary disease. Arch Intern Med. 1983;143:1941–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Gozal D, Row BW, Kheirandish L, et al. Increased susceptibility to intermittent hypoxia in aging rats: changes in proteasomal activity, neuronal apoptosis and spatial function. J Neurochem. 2003;86:1545–52.PubMedCrossRefGoogle Scholar
  47. 47.
    Dayyat EA, Zhang SX, Wang Y, et al. Exogenous erythropoietin administration attenuates intermittent hypoxia-induced cognitive deficits in a murine model of sleep apnea. BMC Neuroscience. 2012;13:77.PubMedCrossRefGoogle Scholar
  48. 48.
    Decker MJ, Hue GE, Caudle WM, et al. Episodic neonatal hypoxia evokes executive dysfunction and regionally specific alterations in markers of dopamine signaling. Neuroscience. 2003;117:417–25.PubMedCrossRefGoogle Scholar
  49. 49.
    Aloia MS, Arnedt JT, Davis JD, et al. Neuropsychological sequelae of obstructive sleep apnea-hypopnea syndrome: a critical review. J Int Neuropsychol Soc. 2004;10:772–85.PubMedCrossRefGoogle Scholar
  50. 50.
    Bucks RS, Olaithe M, Eastwood P. Neurocognitive function in obstructive sleep apnoea: a meta-review. Respirology. 2013;18:61–70.PubMedCrossRefGoogle Scholar
  51. 51.
    Lau EY, Eskes GA, Morrison DL, et al. Executive function in patients with obstructive sleep apnea treated with continuous positive airway pressure. J Int Neuropsychol Soc. 2010;16:1077–88.PubMedCrossRefGoogle Scholar
  52. 52.
    Ju G, Yoon I-Y, Lee SD, et al. Effects of sleep apnea syndrome on delayed memory and executive function in elderly adults. J Am Geriatr Soc. 2012;60:1099–103.PubMedCrossRefGoogle Scholar
  53. 53.
    Spira AP, Blackwell T, Stone KL, et al. Sleep-disordered breathing and cognition in older women. J Am Geriatr Soc. 2008;56:45–50.PubMedCrossRefGoogle Scholar
  54. 54.
    Blackwell T, Yaffe K, Ancoli-Israel S, et al. Associations between sleep architecture and sleep-disordered breathing and cognition in older community-dwelling men: the Osteoporotic Fractures in Men Sleep Study. J Am Geriatr Soc. 2011;59:2217–25.PubMedCrossRefGoogle Scholar
  55. 55.
    Foley D, Monjan A, Masaki K, et al. Daytime sleepiness is associated with 3-year incident dementia and cognitive decline in older Japanese-American men. J Am Geriatr Soc. 2001;49:1628–32.PubMedCrossRefGoogle Scholar
  56. 56.••
    Yaffe K, Laffan AM, Harrison SL, et al. Sleep-disordered breathing, hypoxia, and risk for mild cognitive impairment and dementia in older women. JAMA. 2011;306:613–9. This is the most recent and most comprehensive population-based longitudinal study demonstrating an association between sleep apnea and incident cognitive impairment. PubMedCrossRefGoogle Scholar
  57. 57.
    Tractenberg RE, Singer CM, Kaye JA. Symptoms of sleep disturbance in persons with Alzheimer’s disease and normal elderly. J Sleep Res. 2005;14:177–85.PubMedCrossRefGoogle Scholar
  58. 58.
    Tractenberg RE, Singer CM, Kaye JA. Characterizing sleep problems in persons with Alzheimer’s disease and normal elderly. J Sleep Res. 2006;15:97–103.PubMedCrossRefGoogle Scholar
  59. 59.
    Zimmerman ME, Aloia MS. A review of neuroimaging in obstructive sleep apnea. J Clin Sleep Med. 2006;2:461–71.PubMedGoogle Scholar
  60. 60.
    Kumar R, Birrer BVX, Macey PM, et al. Reduced mammillary body volume in patients with obstructive sleep apnea. Neurosci Letters. 2008;438:330–4.CrossRefGoogle Scholar
  61. 61.
    Macey PM, Kumar R, Woo MA, et al. Brain structural changes in obstructive sleep apnea. Sleep. 2008;31:967–77.PubMedGoogle Scholar
  62. 62.
    Kim H, Yun CH, Thomas RL, et al. Obstructive sleep apnea as a risk factor for cerebral white matter change in a middle-aged and older general population. Sleep. 2013;36:709–15B.PubMedGoogle Scholar
  63. 63.
    Joo EY, Jeon S, Kim ST, et al. Localized cortical thinning in patients with obstructive sleep apnea syndrome. Sleep. 2013;36:1153–62.PubMedGoogle Scholar
  64. 64.
    Canessa N, Castronovo V, Cappa SF, et al. Obstructive sleep apnea: brain structural changes and neurocognitive function before and after treatment. Am J Respir Crit Care Med. 2011;183:1419–26.PubMedCrossRefGoogle Scholar
  65. 65.
    Zhang X, Ma L, Li S, et al. A functional MRI evaluation of frontal dysfunction in patients with severe sleep apnea. Sleep Med. 2011;12:335–40.PubMedCrossRefGoogle Scholar
  66. 66.
    Thomas RJ, Rosen BR, Stern CE, et al. Functional imaging of working memory in obstructive sleep-disordered breathing. J Appl Physiol. 2005;98:2226–34.PubMedCrossRefGoogle Scholar
  67. 67.
    Ayalon L, Ancoli-Israel S, Klemfuss Z, et al. Increased brain activation during verbal learning in obstructive sleep apnea. Neuroimage. 2006;31:1817–25.PubMedCrossRefGoogle Scholar
  68. 68.
    Archbold KH, Borghesani PR, Mahurin RK, et al. Neural activation patterns during working memory tasks and OSA disease severity. J Clin Sleep Med. 2009;5:21–7.PubMedGoogle Scholar
  69. 69.
    Lee SD, Ju G, Kim J-W, et al. Improvement of EEG slowing in OSAS after CPAP treatment. J Psychosom Res. 2012;73:126–31.PubMedCrossRefGoogle Scholar
  70. 70.
    Sharafkhaneh A, Giray N, Richardson P, et al. Association of psychiatric disorders and sleep apnea in a large cohort. Sleep. 2005;28:1405–11.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of NeurologyEmory University School of MedicineAtlantaUSA

Personalised recommendations