Skip to main content
    • Aa
    • Aa

Associations between depression, sleep disturbance, and apolipoprotein E in the development of Alzheimer's disease: dementia

  • Shanna L. Burke (a1), Peter Maramaldi (a2) (a3) (a4), Tamara Cadet (a2) (a3) and Walter Kukull (a5)
ABSTRACT Background:

Alzheimer's disease (AD) is a neurodegenerative brain disease that causes cognitive impairment and dementia. Within the US, AD is the most common form of dementia in the elderly, affecting 1 in 10 people over the age of 65. Sleep disturbance has been called a “public health epidemic” and, like depression, is a prodromal symptom of AD but may also contribute to the risk of developing AD. It was hypothesized that sleep disturbance, depression, and the apolipoprotein E (APOE) genotype increase the likelihood of AD.


Utilizing data from the National Alzheimer's Coordinating Center, information from evaluations of 11,453 cognitively asymptomatic participants was analyzed. Survival analysis was used to explore the independent relationships between depression, sleep disturbance, and APOE genotypes with eventual AD diagnosis. Cox proportional hazard models were utilized to explore the main effects and synergistic effects of psychosocial factors as moderated by APOE genotypes.


This study reinforced the association between APOE and AD. The hazard of developing AD was eight times higher for those with recent depression and the Ɛ4 homozygote (HR = 8.15 [3.70–17.95]). Among Ɛ4 carriers with clinician-verified depression, the hazard was ten times that of the reference group (HR = 10.11 [4.43–23.09]). The hazard for Ɛ4 carriers reporting sleep disturbance was almost 7 times greater than the reference group (HR = 6.79 [2.38–19.37]).


Findings suggest that sleep disturbance, depression, and APOE Ɛ4 genotype are associated with AD during follow-up evaluations among a group of initially cognitively asymptomatic participants. This study contributes to the literature base exploring an increased hazard or risk of AD due to potential modifiable risk factors as well as genetic biomarkers, such as APOE.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Associations between depression, sleep disturbance, and apolipoprotein E in the development of Alzheimer's disease: dementia
      Available formats
      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your Dropbox account. Find out more about sending content to Dropbox.

      Associations between depression, sleep disturbance, and apolipoprotein E in the development of Alzheimer's disease: dementia
      Available formats
      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your Google Drive account. Find out more about sending content to Google Drive.

      Associations between depression, sleep disturbance, and apolipoprotein E in the development of Alzheimer's disease: dementia
      Available formats
Corresponding author
Correspondence should be addressed to: Shanna L. Burke, PhD, MSW, LICSW, Florida International University, Robert Stempel College of Public Health and Social Work, School of Social Work, Modesto A. Maidique Campus, 11200 S.W. 8th Street, AHC5 564, Miami, Florida 33199, USA. Phone: +305-348-7462. Email:
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

D. Barnes and K. Yaffe (2011). The projected effect of risk factor reduction on Alzheimer's disease prevalence. Lancet Neurology, 10, 819828. doi: 10.1016/S1474-4422(11)70145-4.

R. Bateman et al. (2012). Clinical and biomarker changes in dominantly inherited Alzheimer's disease. New England Journal of Medicine, 367, 795804.

C. J. Brainerd , V. F. Reyna , R. C. Petersen , G. E. Smith and E. S. Taub (2011). Is the apolipoprotein e genotype a biomarker for mild cognitive impairment? Findings from a nationally representative study. Neuropsychology, 25, 679689. doi: 10.1037/a0024483.

J. D. Buckley (1984). Additive and multiplicative models for relative survival rates. Biometrics, 40, 5162.

E. H. Corder et al. (1994). Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nature Genetics, 7, 181184.

F. F. de Oliveira , P. H. Ferreira Bertolucci , E. S. Chen and M. C. Smith (2014). Assessment of risk factors for earlier onset of sporadic Alzheimer's disease dementia. Neurology India, 62, 625630. doi:10.4103/0028-3886.149384.

M. Donix , G. W. Small and S. Y. Bookheimer (2012). Family history and APOE-4 genetic risk in Alzheimer's disease. Neuropsychological Review, 22, 298309. doi: 10.1007/s11065-012-9193-2.

B. Efron (1977). The efficiency of Cox's likelihood function for censored data. Journal of the American Statistical Association, 72, 557565.

L. A. Farrer et al. (1997). Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. JAMA, 278, 13491356.

N. Ghebranious et al. (2011). A pilot study of gene/gene and gene/environment interactions in Alzheimer disease. Clinical Medicine & Research, 9, 1725. doi: 10.3I2l/cmr.20I0.894.

D. G. Harwood , W. W. Barker , R. L. Ownby , M. Mullan and R. Duara (2004). No association between subjective memory complaints and apolipoprotein E genotype in cognitively intact elderly. International Journal of Geriatric Psychiatry, 19, 11311139. doi:10.1002/gps.1193.

P. Hollingworth , D. Harold , L. Jones , M. J. Owen and J. Williams (2011). Alzheimer's disease genetics: current knowledge and future challenges. International Journal of Geriatric Psychiatry, 26, 793802. doi: 10.1002/gps.2628.

P. Hollingworth et al. (2006). Four components describe behavioral symptoms in 1,120 individuals with late-onset Alzheimer's disease. Journal of the American Geriatrics Society, 54, 13481354.

D. I. Kaufer et al. (2000). Validation of the NPI-Q: a brief clinical form of the neuropsychiatric inventory. The Journal of Neuropsychiatry and Clinical Neurosciences, 12, 233239.

A. Kumar and P. Chanana (2014). Sleep reduction: a link to other neurobiological diseases. Sleep and Biological Rhythms, 12, 150161. doi:10.1111/sbr.12066.

H. J. Lee and E. Dugan (2015). How large is the gap between self-report and assessed mental health and does it impact older adult mental health service utilization?. Journal of Gerontological Social Work, 58, 319. doi:10.1080/01634372.2014.919978.

A. Lim , L. Yu , M. Kowgier , J. Schneider , A. Buchman and D. Bennett (2013). Modification of the relationship of the apolipoprotein E ε4 allele to the risk of Alzheimer disease and neurofibrillary tangle density by sleep. JAMA Neurology, 70, 15441551. doi:10.1001/jamaneurol.–.4215.

M. Luciano et al. (2015). Current versus lifetime depression, APOE variation, and their interaction on cognitive performance in younger and older adults. Psychosomatic Medicine, 77, 480492. doi: 10.1097/PSY.0000000000000190.

C. G. Lyketsos and J. Olin (2002). Depression in Alzheimer's disease: overview and treatment. Biological Psychiatry, 52, 243252.

G. McKhann , D. Drachman , M. Folstein , R. Katzman , D. Price and E. M. Stadlan (1984). Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of department of health and human services task force on Alzheimer's disease. Neurology, 34, 939944.

J. C. Morris et al. (2006). The uniform data set (UDS): clinical and cognitive variables and descriptive data from Alzheimer's disease centers. Alzheimer Disease and Associated Disorders, 20, 210216.

M. Multhammer , A. Michels , M. Zintl , M. C. Mendoza and H. H. Klünemann (2014). A large ApoE ε4/ε4 homozygous cohort reveals no association with Parkinson's disease. Acta Neurologica Belgica, 114, 2531.

R. S. Osorio et al. (2014). The interaction between sleep-disordered breathing and apolipoprotein E genotype on cerebrospinal fluid biomarkers for Alzheimer's disease in cognitively normal elderly individuals. Neurobiology of Aging, 35, 13181324. doi:10.1016/j.neurobiolaging.2013.12.030.

G. M. Peavy et al. (2007). The effects of prolonged stress and APOE genotype on memory and cortisol in older adults. Biological Psychiatry, 62, 472478.

M. Pistacchi , M. Gioulis , F. Contin , F. Sanson and S. Z. Marsala (2014). Sleep disturbance and cognitive disorder: epidemiological analysis in a cohort of 263 patients. Journal of the Neurological Sciences. doi: 10.1007/s10072-014-1870-x.

A. Saunders et al. (1993). Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease, Neurology, 43, 14671472.

H. M. Schipper (2011). Apolipoprotein E: implications for AD neurobiology, epidemiology and risk assessment. Neurobiology of Aging, 32, 778790. doi:10.1016/j.neurobiolaging.2009.04.021.

R. A. Sperling et al. (2011). Toward defining the preclinical stages of Alzheimer's disease: recommendations from the national institute on aging-Alzheimer's association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer's & Dementia, 7, 280292. doi:10.1016/j.jalz.2011.03.003.

S. Weintraub et al. (2009). The Alzheimer's disease centers’ uniform data set (UDS): the neuropsychological test battery. Alzheimer Disease and Associated Disorders, 23, 91. doi: 10.1097/WAD.0b013e31819c7dd.

D. A. Weldemichael and G. T. Grossberg (2010). Circadian rhythm disturbances in patients with Alzheimer's disease: a review. International Journal of Alzheimer's Disease, 2010, 19. doi:10.4061/2010/716453.

L. Xie et al. (2013). Sleep drives metabolite clearance from the adult brain. Science, 342, 373377. doi:10.1126/science.1241224.

J. A. Yesavage et al. (2004). Sleep/Wake disruption in Alzheimer's disease: APOE status and longitudinal course. Journal of Geriatric Psychiatry & Neurology, 17, 2024. doi:10.1177/0891988703261994.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

International Psychogeriatrics
  • ISSN: 1041-6102
  • EISSN: 1741-203X
  • URL: /core/journals/international-psychogeriatrics
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 110
Total number of PDF views: 454 *
Loading metrics...

Abstract views

Total abstract views: 1062 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 20th September 2017. This data will be updated every 24 hours.