Exploring prior diseases associated with incident late-onset Alzheimer’s disease dementia

Autoři: Jung-Yu Liao aff001;  Charles Tzu-Chi Lee aff001;  Tsung-Yi Lin aff001;  Chin-Mei Liu aff001
Působiště autorů: Department of Health Promotion and Health Education, National Taiwan Normal University, Taipei, Taiwan aff001;  Department of Marketing and Distribution Management, Hsing Wu University, New Taipei City, Taiwan aff002;  Taiwan Centers for Disease Control, Taipei, Taiwan aff003
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0228172


Studies have identified prior conditions associated with late-onset Alzheimer’s disease dementia (LOAD), but all prior diseases have rarely been screened simultaneously in the literature. Our objective in the present study was to identify prior conditions associated with LOAD and construct pathways for them. We conducted a population-based matched case-control study based on data collected in the National Health Insurance Research database of Taiwan and the Catastrophic Illness Certificate database for the years 1997–2013. Prior diseases definitions were based on the first three digits of the codes listed in the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Inclusion criteria required that each ICD-code existed for at least 1 year and incurred at least 2 outpatient visits or inpatient diagnosis. The case group comprised 4,600 patients newly diagnosed with LOAD in 2007–2013. The LOAD patients were matched by sex and age to obtain 4,600 controls. Using stepwise multivariate logistic regression analysis, diseases were screened for 1, 2 …, 9 years prior to the first diagnosis of LOAD. Path analysis was used to construct pathways between prior diseases and LOAD. Our results revealed that the following conditions were positively associated with the incidence of LOAD: anxiety (ICD-code 300), functional digestive disorder (ICD code 564), psychopathology-specific symptoms (ICD-code 307), disorders of the vestibular system (ICD-code 386), concussion (ICD-code 850), disorders of the urethra and urinary tract (ICD-code 599), disorders of refraction and accommodation (ICD-code 367), and hearing loss (ICD-code 389). A number of the prior diseases have previously been described in the literature in a manner identical to that in the present study. Our study supports the assertion that mental, hearing, vestibular system, and functional digestive disorders may play an important role in the pathogenesis of LOAD.

Klíčová slova:

Alzheimer's disease – Anxiety – Deafness – Depression – Epidemiology – Renal system – Skin infections – Taiwan


1. Christensen K, Doblhammer G, Rau R, Vaupel JW. Ageing populations: the challenges ahead. The Lancet. 2009;374(9696):1196–208. doi: https://doi.org/10.1016/S0140-6736(09)61460-4

2. Alzheimer's disease international. Available from: https://www.alz.co.uk/about-dementia

3. Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer's disease. Lancet. 2011;377(9770):1019–31. Epub 2011/03/05. doi: 10.1016/S0140-6736(10)61349-9 21371747.

4. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. The Lancet Neurology. 2006;5(3):228–34. doi: 10.1016/S1474-4422(06)70355-6 16488378

5. Wen YH, Wu SS, Lin CH, Tsai JH, Yang P, Chang YP, et al. A Bayesian Approach to Identifying New Risk Factors for Dementia: A Nationwide Population-Based Study. Medicine (Baltimore). 2016;95(21):e3658. Epub 2016/05/27. doi: 10.1097/md.0000000000003658 27227925; PubMed Central PMCID: PMC4902349.

6. Moonga I, Niccolini F, Wilson H, Pagano G, Politis M. Hypertension is associated with worse cognitive function and hippocampal hypometabolism in Alzheimer's disease. European Journal of Neurology. 2017;24(9):1173–82. doi: 10.1111/ene.13374 28752644

7. Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, et al. Dementia prevention, intervention, and care. The Lancet. 2017.

8. Fan YC, Hsu JL, Tung HY, Chou CC, Bai CH. Increased dementia risk predominantly in diabetes mellitus rather than in hypertension or hyperlipidemia: a population-based cohort study. Alzheimers Res Ther. 2017;9(1):7. Epub 2017/02/07. doi: 10.1186/s13195-017-0236-z 28162091; PubMed Central PMCID: PMC5292809.

9. Mah L, Szabuniewicz C, Fiocco AJ. Can anxiety damage the brain? Curr Opin Psychiatry. 2016;29(1):56–63. Epub 2015/12/10. doi: 10.1097/YCO.0000000000000223 26651008.

10. Cole J, Costafreda SG, McGuffin P, Fu CH. Hippocampal atrophy in first episode depression: a meta-analysis of magnetic resonance imaging studies. J Affect Disord. 2011;134(1–3):483–7. Epub 2011/07/13. doi: 10.1016/j.jad.2011.05.057 21745692.

11. Van der Mussele S, Fransen E, Struyfs H, Luyckx J, Marien P, Saerens J, et al. Depression in mild cognitive impairment is associated with progression to Alzheimer's disease: a longitudinal study. Journal of Alzheimer's disease: JAD. 2014;42(4):1239–50. Epub 2014/07/16. doi: 10.3233/JAD-140405 25024328.

12. da Silva J, Goncalves-Pereira M, Xavier M, Mukaetova-Ladinska EB. Affective disorders and risk of developing dementia: systematic review. Br J Psychiatry. 2013;202(3):177–86. Epub 2013/03/05. doi: 10.1192/bjp.bp.111.101931 23457181.

13. Sierksma AS, van den Hove DL, Steinbusch HW, Prickaerts J. Major depression, cognitive dysfunction and Alzheimer's disease: is there a link? Eur J Pharmacol. 2010;626(1):72–82. Epub 2009/10/20. doi: 10.1016/j.ejphar.2009.10.021 19837053.

14. Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy in recurrent major depression. Proceedings of the National Academy of Sciences. 1996;93(9):3908–13.

15. Tolppanen AM, Taipale H, Hartikainen S. Head or brain injuries and Alzheimer's disease: A nested case-control register study. Alzheimer's & dementia: the journal of the Alzheimer's Association. 2017;13(12):1371–9. Epub 2017/06/10. doi: 10.1016/j.jalz.2017.04.010 28599121.

16. Li Y, Li Y, Li X, Zhang S, Zhao J, Zhu X, et al. Head Injury as a Risk Factor for Dementia and Alzheimer's Disease: A Systematic Review and Meta-Analysis of 32 Observational Studies. PloS one. 2017;12(1):e0169650. Epub 2017/01/10. doi: 10.1371/journal.pone.0169650 28068405; PubMed Central PMCID: PMC5221805.

17. Tolppanen AM, Taipale H, Hartikainen S. Head or brain injuries and Alzheimer's disease: A nested case-control register study. Alzheimer's & dementia: the journal of the Alzheimer's Association. 2017. Epub 2017/06/10. doi: 10.1016/j.jalz.2017.04.010 28599121.

18. Zheng Y, Fan S, Liao W, Fang W, Xiao S, Liu J. Hearing impairment and risk of Alzheimer's disease: a meta-analysis of prospective cohort studies. Neurol Sci. 2017;38(2):233–9. Epub 2016/11/30. doi: 10.1007/s10072-016-2779-3 27896493.

19. Thomson RS, Auduong P, Miller AT, Gurgel RK. Hearing loss as a risk factor for dementia: A systematic review. Laryngoscope Investig Otolaryngol. 2017;2(2):69–79. Epub 2017/09/13. doi: 10.1002/lio2.65 28894825; PubMed Central PMCID: PMC5527366.

20. Su P, Hsu CC, Lin HC, Huang WS, Yang TL, Hsu WT, et al. Age-related hearing loss and dementia: a 10-year national population-based study. Eur Arch Otorhinolaryngol. 2017;274(5):2327–34. Epub 2017/02/24. doi: 10.1007/s00405-017-4471-5 28229293.

21. Deal JA, Betz J, Yaffe K, Harris T, Purchase-Helzner E, Satterfield S, et al. Hearing Impairment and Incident Dementia and Cognitive Decline in Older Adults: The Health ABC Study. J Gerontol A Biol Sci Med Sci. 2017;72(5):703–9. Epub 2016/04/14. doi: 10.1093/gerona/glw069 27071780.

22. Lin FR, Ferrucci L, Metter EJ, An Y, Zonderman AB, Resnick SM. Hearing loss and cognition in the Baltimore Longitudinal Study of Aging. Neuropsychology. 2011;25(6):763–70. Epub 2011/07/07. doi: 10.1037/a0024238 21728425; PubMed Central PMCID: PMC3193888.

23. Lin FR, Metter EJ, O'Brien RJ, Resnick SM, Zonderman AB, Ferrucci L. Hearing loss and incident dementia. Arch Neurol. 2011;68(2):214–20. Epub 2011/02/16. doi: 10.1001/archneurol.2010.362 21320988; PubMed Central PMCID: PMC3277836.

24. Guthrie DM, Davidson JGS, Williams N, Campos J, Hunter K, Mick P, et al. Combined impairments in vision, hearing and cognition are associated with greater levels of functional and communication difficulties than cognitive impairment alone: Analysis of interRAI data for home care and long-term care recipients in Ontario. PloS one. 2018;13(2):e0192971. Epub 2018/02/16. doi: 10.1371/journal.pone.0192971 29447253; PubMed Central PMCID: PMC5814012.

25. Hughes SE, Hutchings HA, Rapport FL, McMahon CM, Boisvert I. Social Connectedness and Perceived Listening Effort in Adult Cochlear Implant Users: A Grounded Theory to Establish Content Validity for a New Patient-Reported Outcome Measure. Ear Hear. 2018. Epub 2018/02/10. doi: 10.1097/aud.0000000000000553 29424766.

26. Dawes P, Emsley R, Cruickshanks KJ, Moore DR, Fortnum H, Edmondson-Jones M, et al. Hearing loss and cognition: the role of hearing AIDS, social isolation and depression. PloS one. 2015;10(3):e0119616. Epub 2015/03/12. doi: 10.1371/journal.pone.0119616 25760329; PubMed Central PMCID: PMC4356542.

27. Liu CM, Lee CT. Association of Hearing Loss With Dementia. JAMA network open. 2019;2(7):e198112. Epub 2019/08/01. doi: 10.1001/jamanetworkopen.2019.8112 31365110.

28. Chen CH, Lin CL, Kao CH. Irritable Bowel Syndrome Is Associated with an Increased Risk of Dementia: A Nationwide Population-Based Study. PloS one. 2016;11(1):e0144589. Epub 2016/01/06. doi: 10.1371/journal.pone.0144589 26731277; PubMed Central PMCID: PMC4701489.

29. Kowalski K, Mulak A. Brain-Gut-Microbiota Axis in Alzheimer's Disease. Journal of neurogastroenterology and motility. 2019;25(1):48–60. Epub 2019/01/17. doi: 10.5056/jnm18087 30646475; PubMed Central PMCID: PMC6326209.

30. Szablewski L. Human Gut Microbiota in Health and Alzheimer's Disease. Journal of Alzheimer's disease: JAD. 2018;62(2):549–60. Epub 2018/02/27. doi: 10.3233/JAD-170908 29480188.

31. Institutes. NHR. National Health Insurance Research Database. [cited 2017 Oct 2]. Available from: http://nhird.nhri.org.tw/date_01_en.html

32. Hooper D, Coughlan J, Mullen M. Structural equation modelling: Guidelines for determining model fit. Articles. 2008:2.

33. Tsai CP, Hu C, Lee CT. Finding diseases associated with amyotrophic lateral sclerosis: a total population-based case-control study. Amyotrophic lateral sclerosis & frontotemporal degeneration. 2019;20(1–2):82–9. Epub 2018/11/14. doi: 10.1080/21678421.2018.1522354 30422689.

34. Moon B, Kim S, Park YH, Lim JS, Youn YC, Kim S, et al. Depressive Symptoms are Associated with Progression to Dementia in Patients with Amyloid-Positive Mild Cognitive Impairment. Journal of Alzheimer's disease: JAD. 2017;58(4):1255–64. Epub 2017/05/28. doi: 10.3233/JAD-170225 28550264.

35. Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D. Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry. 2006;63(5):530–8. Epub 2006/05/03. doi: 10.1001/archpsyc.63.5.530 16651510; PubMed Central PMCID: PMC3530614.

36. Tapiainen V, Hartikainen S, Taipale H, Tiihonen J, Tolppanen AM. Hospital-treated mental and behavioral disorders and risk of Alzheimer's disease: A nationwide nested case-control study. Eur Psychiatry. 2017;43:92–8. Epub 2017/04/08. doi: 10.1016/j.eurpsy.2017.02.486 28388490.

37. Lucieer F, Duijn S, Van Rompaey V, Perez Fornos A, Guinand N, Guyot JP, et al. Full Spectrum of Reported Symptoms of Bilateral Vestibulopathy Needs Further Investigation-A Systematic Review. Front Neurol. 2018;9:352. Epub 2018/06/20. doi: 10.3389/fneur.2018.00352 29915554; PubMed Central PMCID: PMC5994412.

38. Lucieer F, Vonk P, Guinand N, Stokroos R, Kingma H, van de Berg R. Bilateral Vestibular Hypofunction: Insights in Etiologies, Clinical Subtypes, and Diagnostics. Front Neurol. 2016;7:26. Epub 2016/03/15. doi: 10.3389/fneur.2016.00026 26973594; PubMed Central PMCID: PMC4777732.

39. Strupp M. Challenges in neuro-otology. Front Neurol. 2010;1:121. Epub 2011/01/06. doi: 10.3389/fneur.2010.00121 21206521; PubMed Central PMCID: PMC3009447.

40. Previc FH. Vestibular loss as a contributor to Alzheimer's disease. Med Hypotheses. 2013;80(4):360–7. Epub 2013/02/05. doi: 10.1016/j.mehy.2012.12.023 23375669.

41. Davies HR, Cadar D, Herbert A, Orrell M, Steptoe A. Hearing Impairment and Incident Dementia: Findings from the English Longitudinal Study of Ageing. J Am Geriatr Soc. 2017;65(9):2074–81. Epub 2017/07/25. doi: 10.1111/jgs.14986 28734053.

42. Shen Y, Ye B, Chen P, Wang Q, Fan C, Shu Y, et al. Cognitive Decline, Dementia, Alzheimer's Disease and Presbycusis: Examination of the Possible Molecular Mechanism. Front Neurosci. 2018;12:394. Epub 2018/06/26. doi: 10.3389/fnins.2018.00394 29937713; PubMed Central PMCID: PMC6002513.

43. Organization WH. International statistical classification of diseases and related health problems: World Health Organization; 2004.

44. Bate A. Guidance to reinforce the credibility of health care database studies and ensure their appropriate impact. Pharmacoepidemiol Drug Saf. 2017;26(9):1013–7. Epub 2017/09/16. doi: 10.1002/pds.4305 28913965.

45. Martin S, Kelly S, Kuhn I, Cowan A, Brayne C. Disbility, dementia and fraility in later lofe: mid-life approaches to prevent or delay the ontset of these conditions: Cambridge Institute of Public Health, University of Cambridge; 2014 [cited 2017 Oct 7]. Available from: http://www.iph.cam.ac.uk

46. Lin F-C, Chuang Y-S, Hsieh H-M, Lee T-C, Chiu K-F, Liu C-K, et al. Early statin use and the progression of Alzheimer disease: a total population-based case-control study. Medicine. 2015;94(47).

47. Campbell J, Sharma A. Compensatory changes in cortical resource allocation in adults with hearing loss. Front Syst Neurosci. 2013;7:71. Epub 2014/01/31. doi: 10.3389/fnsys.2013.00071 24478637; PubMed Central PMCID: PMC3905471.

48. Ronnberg J, Rudner M, Lunner T, Zekveld AA. When cognition kicks in: working memory and speech understanding in noise. Noise Health. 2010;12(49):263–9. Epub 2010/09/28. doi: 10.4103/1463-1741.70505 20871181.

49. Boyle PA, Wilson RS, Schneider JA, Bienias JL, Bennett DA. Processing resources reduce the effect of Alzheimer pathology on other cognitive systems. Neurology. 2008;70(17):1534–42. Epub 2008/03/21. doi: 10.1212/01.wnl.0000304345.14212.38 18354077.

50. Lin FR, Yaffe K, Xia J, Xue QL, Harris TB, Purchase-Helzner E, et al. Hearing loss and cognitive decline in older adults. JAMA Intern Med. 2013;173(4):293–9. Epub 2013/01/23. doi: 10.1001/jamainternmed.2013.1868 23337978; PubMed Central PMCID: PMC3869227.

51. Smith PA. The tantalizing links between gut microbes and the brain. Nature. 2015;526(7573):312–4. Epub 2015/10/16. doi: 10.1038/526312a 26469024.

52. Foster JA, McVey Neufeld KA. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013;36(5):305–12. Epub 2013/02/07. doi: 10.1016/j.tins.2013.01.005 23384445.

53. Daulatzai MA. Chronic functional bowel syndrome enhances gut-brain axis dysfunction, neuroinflammation, cognitive impairment, and vulnerability to dementia. Neurochem Res. 2014;39(4):624–44. Epub 2014/03/05. doi: 10.1007/s11064-014-1266-6 24590859.

54. Carabotti M, Scirocco A, Maselli MA, Severi C. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol. 2015;28(2):203–9. Epub 2015/04/02. 25830558; PubMed Central PMCID: PMC4367209.

55. Powell N, Walker MM, Talley NJ. The mucosal immune system: master regulator of bidirectional gut-brain communications. Nat Rev Gastroenterol Hepatol. 2017;14(3):143–59. Epub 2017/01/18. doi: 10.1038/nrgastro.2016.191 28096541.

56. Fung TC, Olson CA, Hsiao EY. Interactions between the microbiota, immune and nervous systems in health and disease. Nat Neurosci. 2017;20(2):145–55. Epub 2017/01/17. doi: 10.1038/nn.4476 28092661.

57. Bu XL, Yao XQ, Jiao SS, Zeng F, Liu YH, Xiang Y, et al. A study on the association between infectious burden and Alzheimer's disease. Eur J Neurol. 2015;22(12):1519–25. Epub 2014/06/10. doi: 10.1111/ene.12477 24910016.

58. Leue C, Kruimel J, Vrijens D, Masclee A, van Os J, van Koeveringe G. Functional urological disorders: a sensitized defence response in the bladder-gut-brain axis. Nat Rev Urol. 2017;14(3):153–63. Epub 2016/12/07. doi: 10.1038/nrurol.2016.227 27922040.

Článek vyšel v časopise


2020 Číslo 1
Nejčtenější tento týden