重要性
失智症為全球最失能與高經濟負擔的健康狀況之一，而阿茲海默病是失智症主要類型。之前的研究雖陸續發表與晚發型阿茲海默( Late-Onset Alzheimer’s Disease, LOAD)失智症相關之危險或保護的共病症，但罕見同時探討所有被診斷的相關共病症。
目的
本研究探討與LOAD失智症相關之危險或保護的共病症，並建構相關共病症和LOAD失智症之間的關係路徑。最後分析有耳聾患者其之後發生失智症的風險。
研究設計
進行全國人口為對象之配對病例對照研究及配對世代研究，並以第一次被診斷為LOAD失智症及第一次診斷耳聾為研究基準日。
資料來源
使用全民健康保險研究資料庫及重大傷病資料庫。
對象
台灣於2007-2013年重大傷病資料中之新診斷LOAD病患及2000-2011年新診斷健保資料耳聾的病患。病例對照研究以性別、年齡進行配對以選取控制組病患；世代研究以性別、年齡、投保薪資及居住地區進行配對。配對比例均為1:1。

暴露因子
篩選在診斷為LOAD失智症日期之前所有被診斷過去共病症，前述共病症認定以國際疾病分類第九版前三碼為準。另篩選新診斷耳聾症。
主要結果測量
LOAD失智症、失智症。
統計方法
(1)卡方或T檢定用於比較LOAD失智症新診斷病例與對照組之間的人口學差異。相關共病症透過多變數條件邏輯斯迴歸及逐步篩選法來進行篩選，顯著相關共病症認定為經多變數校正後之P值小於0.05。P值係執行雙尾檢定所得。
(2)路徑分析用於構建相關共病症和LOAD失智症之間的路徑，分別建構診斷1年之前及診斷4年之前的正、負及最後模型之相關路徑，並分析估計在滿足整體適合度指數(goodness of fit model) 達理想建議值的範圍，最後修正模型(Final model)中各共病症相關路徑間的路徑係數。
(3)使用存活分析計算有無耳聾世代之累積發生率，Cox比例風險模型計算有耳聾診斷的世代於調整干擾因子後發生失智症之風險(Hazard Ratio，HR)。顯著相關認定為經多變數及多重比較校正(False Discovery Rate, FDR)後之P值小於0.05。另以傾向分數配對法進行敏感性分析。
結果
(1)以第一次被診斷為LOAD失智症為研究基準日回溯篩選，在其診斷1年以前，總計有42項過去共病症與LOAD失智症呈顯著相關，其中25項為正相關，17項為負相關。在LOAD失智症診斷4年以前，總計有26項過去共病症與LOAD失智症呈顯著相關，其中19項為正相關，7項為負相關。
(2)在滿足整體適合度指數達理想建議值的範圍，於診斷1年之前及診斷4年之前的最後修正模型中，處於模式路徑的上層位置有4項過去共病症(ICD codes 300焦慮; ICD codes 307特殊症狀或徵候群心理疾患; ICD codes 564功能性消化道疾病; ICD codes 386眩暈徵候群及其他前庭系統之疾患)，且此4個共病症在1年之前及診斷4年之前的2項模型內，比其它相關共病症對LOAD的總影響力也是較大的。此外，3項共病症(ICD codes 564、386及389耳聾)為模式中其他多個共病症的常見中間變項。
(3)存活分析顯示，在觀察期間，耳聾患者累積失智症發生率比非耳聾患者顯著高(p < 0.001, log-rank test)，耳聾患者比非耳聾者的失智症發生率高 (耳聾：19.38 , 95% CI, 18.25-20.57; 非耳聾13.98, 95% CI,13.01-15.00，單位: 1000 person-year)。在控制潛在的干擾變項後，Cox迴歸模型分析顯示，耳聾與患失智症有顯著正相關(HR = 1.14, 95% CI, 1.04 - 1.25; p= 0.007, FDR p= 0.014)。年齡增加和高門診頻率與患失智症均呈顯著正相關(HR = 2.53, 95% CI, 2.40 - 2.67, FDR p< 0.001; HR = 1.05, 95% CI, 1.03 - 1.08; FDR p< 0.001)，投保薪資2萬及以上與失智顯著呈負相關(HR = 0.71, 95% CI, 0.62 - 0.81; p< 0.001, FDR p< 0.001)。 此外，心血管疾病、糖尿病、焦慮、憂鬱、酒精相關疾病及頭部外傷與發生失智症呈顯著正相關。以三個年齡組( 45-64 歲、65-74 歲、≥75 歲)的分層分析結果顯示，45-64歲組患失智的風險顯著高於其他年齡組(HR = 2.14, 95% CI, 1.51 - 3.03, FDR p <0.001)。根據敏感性分析結果，耳聾仍為發生失智症的危險因子(HR = 1.2, 95% CI, 1.09 - 1.31; FDR p< 0.001)，45-64歲組及65-74 歲組具患失智風險(HR = 1.44, 95% CI, 1.16 - 1.8, FDR p= 0.004; HR = 1.24, 95% CI, 1.07 - 1.45, FDR p=0.021)。
結論
本研究篩選出42項與LOAD相關的過去共病症，推測部分共病症為LOAD失智症之前驅期病症如焦慮、特殊症狀或徵候群心理疾患、情感性精神病、耳聾及大腦退化等(ICD codes 300、307、296、389及331)，對LOAD發生的總影響力也是較大。於神經精神疾病、功能性消化道疾病、眩暈徵候群及前庭系統之疾患及耳聾等疾病的相關路徑(ICD codes 300、307、296、386及389)支持“腸 - 腦軸”或“腦 - 腸軸”雙向通信系統作用在LOAD發生扮演重要角色。在世代研究分析顯示，耳聾是患失智症的顯著風險因子，特別是在45-64歲的族群。因此，聽力保護、篩檢及早期治療應視考慮列入預防失智症的策略之一。

Importance
Dementia is one of the most debilitating and burdensome health conditions worldwide. Alzheimer’s disease is a major type of dementia. Although studies have found some risk or protective factors regarding comorbidities associated with late-onset Alzheimer’s disease (LOAD), all comorbidities have rarely been screened simultaneously in the literature.
Purpose
The present study attempts to determine prior comorbidities associated with LOAD and construct pathways for these comorbidities. In addition, the incidence risk of all types of dementia in patients with hearing-loss was investigated.
Study design
We conducted a total population-based matched case–control study and a population-based matched cohort study. The index date was set as the first diagnosis date of LOAD and hearing loss.
Data source
Data were collected from Taiwan’s National Health Insurance Research Database and Catastrophic Illness Database.
Study participants
The study participants included patients newly diagnosed with dementia (International Classification of Diseases, ninth revision, ICD-9-CM code: 290) from 2007 to 2013 and those prescribed any acetylcholinesterase inhibitors (AChEIs; Anatomical Therapeutic Chemical code: N06D) as well as those newly diagnosed with hearing loss (ICD-9-CM codes 389 and A241) from 2000 to 2011. These patients were exactly matched according to sex and age, with a matching ratio of 1:1 for case control study and a matching ratio of 1:1 by sex, age, residence, insurance premium for the cohort study.
Exposures
Prior comorbidities were screened out for 1, 2, 3, 4, 5, 6, 7, 8, 9 years before the first diagnosis of LOAD. Comorbidities were defined according to the first three digits of ICD-9-CM codes. Furthermore, a diagnosis of hearing loss was defined according to ICD-9-CM codes 389, A241.
Main Outcome Measure
LOAD and dementia.
Statistics analysis
(1) Chi-squared or t-tests were performed to examine differences in the demographics and characteristics of patients newly diagnosed with LOAD and those of controls. A conditional logistic regression model was used to identify associated comorbidities. To evaluate the association between these comorbidities and the risk of LOAD by performing stepwise multivariate logistic regression, each significant independent factor was adjusted P < 0.05; all tests were two-sided.
(2)Path analysis was performed to construct the pathways between associated comorbidities and LOAD for 1 and 4 years before the first diagnosis of LOAD. The path coefficients of each pathway were estimated in goodness-of-fit of model.
(3) A Kaplan–Meier analysis was performed to calculate the cumulative incidence of dementia. Cox’s hazards model was used to compute the hazard ratios (HRs) of dementia progression after potential confounding factors were adjusted for in the hearing-loss cohort study. Each significant independent factor was considered as having a false discovery rate (FDR) adjusted p value of < 0.05. To validate the robustness of the main study findings, we performed a sensitivity analysis by matching propensity scores.
Results
(1)Of the total 42 diagnostic prior comorbidities associated with LOAD in 1 year before the first diagnosis date of LOAD, 25 comorbidities had positive effects and 17 comorbidities had negative effects. Moreover, of the 26 comorbidities associated with LOAD in the 4 years before the first diagnosis date, 19 comorbidities had positive effects and 7 comorbidities had negative effects.
(2) In the final model for 1 and 4 years before the first diagnosis date of LOAD, anxiety, psychopathology-specific symptoms, functional digestive disorder, vertiginous syndromes, and disorders of the vestibular system (ICD codes 300, 307, 564, and 386) located at the upper position of final model had stronger positive effects on LOAD incidence than other associated comorbidities. Vertiginous syndromes and disorders of the vestibular system, hearing loss, functional digestive disorder, and disorders of the urethra and urinary tract (ICD codes 564, 386, 389, and 599) were frequent mediators in the model.
(3) In the Kaplan–Meier analysis, cumulative dementia incidence rates were significantly higher in the hearing-loss group than those in the non-hearing-loss group (P < 0.001, log-rank test). The dementia incidence rate in the hearing-loss group was higher than that in the non-hearing-loss group (19.38, 95% CI, 18.25–20.57; 13.98, 95% CI, 13.01–15.00, 1000 person-years) during the follow-up time. After the fully adjusted multivariate cox regression model was applied for risk analysis, it was found that the patients with hearing loss had a significant risk of developing dementia (HR = 1.14, 95%CI, 1.04–1.25; FDR P = 0.014). Increased age and highly frequent outpatient visits were significantly and positively associated with a risk of dementia, but insurance premium amount (NT$20,000 and above per moth) was significantly and negatively associated with dementia. In addition, cerebrovascular disease, diabetes, anxiety, depression, alcohol-related illnesses, and head injury were significantly and positively associated with a risk of dementia (FDR P < 0.01). A stratified analysis of three age groups (45–64 years, 65–74 years, and ≥75 years) showed that the 45–64-year group was at a significantly higher risk of developing dementia than the other age groups (HR = 2.14, 95% CI, 1.51–3.03, FDR P < 0.001). After a sensitivity analysis was performed, it was revealed that patients with hearing loss still had a significant risk of developing dementia (HR = 1.2, 95% CI, 1.09–1.31; FDR P < 0.001), and patients in the 45–64-year and 65–74-year age groups were at a significantly higher risk of developing dementia than those in the ≥75-year age group (HR = 1.44, 95% CI, 1.16–1.8, FDR P = 0.004; HR = 1.24, 95% CI, 1.07–1.45, FDR P = 0.021).
Conclusion
A total of 42 prior comorbidities related to LOAD, such as anxiety, psychopathology-specific symptoms, hearing loss, episodic mood disorders, and cerebral degenerations (ICD codes 300, 307, 296, 389, and 331), before diagnosis were related to prodromal LOAD and yielded a high total positive effect on LOAD. The corrected pathways among neuropsychiatric, digestive, vestibular, and hearing system diseases (ICD codes 300, 307, 564, 386, and 389, respectively) and LOAD may support the gut–brain axis and brain–gut axis causal effect in LOAD pathogenesis. In our cohort study, the results showed that hearing loss is a significant risk predictor for development of dementia, especially among patients in the 45–64 years age group. Hearing protection, screening, and treatment can be employed as the strategies for preventing dementia.

Reference
1. WHO. Dementia. http://www.who.int/mediacentre/factsheets/fs362/en/. Accessed September 26, 2017.
2. Christensen K, Doblhammer G, Rau R, Vaupel JW. Ageing populations: the challenges ahead. The Lancet. 2009;374(9696):1196-1208.
3. Prince M, Wimo A, Guerchet M, Ali G, Wu Y, Prina M. Alzheimer’s Disease International. World Alzheimer Report 2015: The Global Impact of Dementia: an Analysis of Prevalence, Incidence, Cost and Trend. 2016.
4. Lin YY, Huang CS. Aging in Taiwan: Building a Society for Active Aging and Aging in Place. Gerontologist. 2016;56(2):176-183.
5. Deb A, Thornton JD, Sambamoorthi U, Innes K. Direct and indirect cost of managing alzheimer's disease and related dementias in the United States. Expert review of pharmacoeconomics & outcomes research. 2017;17(2):189-202.
6. Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer's disease. Lancet (London, England). 2011;377(9770):1019-1031.
7. 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):228-234.
8. Wen YH, Wu SS, Lin CH, et al. A Bayesian Approach to Identifying New Risk Factors for Dementia: A Nationwide Population-Based Study. Medicine. 2016;95(21):e3658.
9. 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):1173-1182.
10. Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care. The Lancet. 2017.
11. 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. Alzheimer's research & therapy. 2017;9(1):7.
12. Reitz C, Tang M-X, Schupf N, Manly JJ, Mayeux R, Luchsinger JA. A summary risk score for the prediction of Alzheimer disease in elderly persons. Archives of neurology. 2010;67(7):835-841.
13. Association As. 2017 Alzheimer's disease facts and figures. Alzheimer's & Dementia. 2017;13(4):325-373.
14. Li Y, Li Y, Li 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.
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.
16. Mah L, Szabuniewicz C, Fiocco AJ. Can anxiety damage the brain? Current opinion in psychiatry. 2016;29(1):56-63.
17. 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):3908-3913.
18. 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):483-487.
19. Van der Mussele S, Fransen E, Struyfs H, 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):1239-1250.
20. da Silva J, Goncalves-Pereira M, Xavier M, Mukaetova-Ladinska EB. Affective disorders and risk of developing dementia: systematic review. The British journal of psychiatry : the journal of mental science. 2013;202(3):177-186.
21. Sierksma AS, van den Hove DL, Steinbusch HW, Prickaerts J. Major depression, cognitive dysfunction and Alzheimer's disease: is there a link? European journal of pharmacology. 2010;626(1):72-82.
22. 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. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2017;38(2):233-239.
23. Thomson RS, Auduong P, Miller AT, Gurgel RK. Hearing loss as a risk factor for dementia: A systematic review. Laryngoscope investigative otolaryngology. 2017;2(2):69-79.
24. Su P, Hsu CC, Lin HC, et al. Age-related hearing loss and dementia: a 10-year national population-based study. European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery. 2017;274(5):2327-2334.
25. Deal JA, Betz J, Yaffe K, et al. Hearing Impairment and Incident Dementia and Cognitive Decline in Older Adults: The Health ABC Study. The journals of gerontology Series A, Biological sciences and medical sciences. 2017;72(5):703-709.
26. 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):763-770.
27. Lin FR, Metter EJ, O'Brien RJ, Resnick SM, Zonderman AB, Ferrucci L. Hearing loss and incident dementia. Arch Neurol. 2011;68(2):214-220.
28. 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):2074-2081.
29. Organization WH. International statistical classification of diseases and related health problems. Vol 1: World Health Organization; 2004.
30. Prince M, Guerchet M, Prina M. The global impact of dementia 2013-2050. Alzheimer's Disease International; 2013.
31. Wimo A, Guerchet M, Ali G-C, et al. The worldwide costs of dementia 2015 and comparisons with 2010. Alzheimer's & Dementia. 2017;13(1):1-7.
32. Wu Y-T, Lee H-y, Norton S, et al. Prevalence studies of dementia in mainland China, Hong Kong and Taiwan: a systematic review and meta-analysis. PloS one. 2013;8(6):e66252.
33. Sun Y, Lee H-J, Yang S-C, et al. A nationwide survey of mild cognitive impairment and dementia, including very mild dementia, in Taiwan. PloS one. 2014;9(6):e100303.
34. Chen C-H, Wang L-C, Ma T-C, Yang Y-H. A walk-in screening of dementia in the general population in Taiwan. The Scientific World Journal. 2014;2014.
35. Health Promotion Administration MoHaW. Taiwan aging map. 2011; https://www.hpa.gov.tw/Pages/Detail.aspx?nodeid=1131&pid=2276
36. Alzheimer's disease international. https://www.alz.co.uk/about-dementia.
37. Hung YN, Kadziola Z, Brnabic AJ, et al. The epidemiology and burden of Alzheimer's disease in Taiwan utilizing data from the National Health Insurance Research Database. ClinicoEconomics and outcomes research : CEOR. 2016;8:387-395.
38. Barbagallo M, Dominguez LJ. Type 2 diabetes mellitus and Alzheimer’s disease. World journal of diabetes. 2014;5(6):889.
39. Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science (New York, NY). 1993;261(5123):921-923.
40. Luchsinger JA, Mayeux R. Cardiovascular risk factors and Alzheimer’s disease. Current atherosclerosis reports. 2004;6(4):261-266.
41. Kivipelto M, Ngandu T, Laatikainen T, Winblad B, Soininen H, Tuomilehto J. Risk score for the prediction of dementia risk in 20 years among middle aged people: a longitudinal, population-based study. The Lancet Neurology. 2006;5(9):735-741.
42. Chen TB, Yiao SY, Sun Y, et al. Comorbidity and dementia: A nationwide survey in Taiwan. PloS one. 2017;12(4):e0175475.
43. Xu W, Qiu C, Gatz M, Pedersen NL, Johansson B, Fratiglioni L. Mid-and late-life diabetes in relation to the risk of dementia. Diabetes. 2009;58(1):71-77.
44. Profenno LA, Porsteinsson AP, Faraone SV. Meta-analysis of Alzheimer's disease risk with obesity, diabetes, and related disorders. Biological psychiatry. 2010;67(6):505-512.
45. Zhang J, Chen C, Hua S, et al. An updated meta-analysis of cohort studies: Diabetes and risk of Alzheimer's disease. Diabetes research and clinical practice. 2017;124:41-47.
46. 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):1173-1182.
47. Vemuri P, Knopman DS, Lesnick TG, et al. Evaluation of Amyloid Protective Factors and Alzheimer Disease Neurodegeneration Protective Factors in Elderly Individuals. JAMA neurology. 2017;74(6):718-726.
48. Gabin JM, Tambs K, Saltvedt I, Sund E, Holmen J. Association between blood pressure and Alzheimer disease measured up to 27 years prior to diagnosis: the HUNT Study. Alzheimer's research & therapy. 2017;9(1):37.
49. Graham DI, Gentleman SM, Nicoll JA, et al. Altered beta-APP metabolism after head injury and its relationship to the aetiology of Alzheimer's disease. Acta neurochirurgica Supplement. 1996;66:96-102.
50. Franzblau M, Gonzales-Portillo C, Gonzales-Portillo GS, et al. Vascular damage: a persisting pathology common to Alzheimer's disease and traumatic brain injury. Medical hypotheses. 2013;81(5):842-845.
51. Bate A. Guidance to reinforce the credibility of health care database studies and ensure their appropriate impact. Pharmacoepidemiology and drug safety. 2017;26(9):1013-1017.
52. 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. 2014; http://www.iph.cam.ac.uk. Accessed Oct 7, 2017.
53. Lin F-C, Chuang Y-S, Hsieh H-M, et al. Early statin use and the progression of Alzheimer disease: a total population-based case-control study. Medicine. 2015;94(47).
54. Amieva H, Ouvrard C, Meillon C, Rullier L, Dartigues JF. Death, Depression, Disability and Dementia Associated with Self-Reported Hearing Problems: a 25-Year Study. The journals of gerontology Series A, Biological sciences and medical sciences. 2018.
55. Loughrey DG, Kelly ME, Kelley GA, Brennan S, Lawlor BA. Association of Age-Related Hearing Loss With Cognitive Function, Cognitive Impairment, and Dementia: A Systematic Review and Meta-analysis. JAMA otolaryngology-- head & neck surgery. 2018;144(2):115-126.
56. Savitz J, Drevets WC. Bipolar and major depressive disorder: neuroimaging the developmental-degenerative divide. Neuroscience and biobehavioral reviews. 2009;33(5):699-771.
57. Li P, Hsiao IT, Liu CY, et al. Beta-amyloid deposition in patients with major depressive disorder with differing levels of treatment resistance: a pilot study. 2017;7(1):24.
58. Moon B, Kim S, Park YH, 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):1255-1264.
59. Bellou V, Belbasis L, Tzoulaki I, Middleton LT, Ioannidis JP, Evangelou E. Systematic evaluation of the associations between environmental risk factors and dementia: An umbrella review of systematic reviews and meta-analyses. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2017;13(4):406-418.
60. Institutes. NHR. National Health Insurance Research Database. http://nhird.nhri.org.tw/date_01_en.html. Accessed Oct 2, 2017.
61. Administration NHI. Categories of catastrophic illness. https://www.nhi.gov.tw/Content_List.aspx?n=3AE7F036072F88AF&topn=D39E2B72B0BDFA15. Accessed Oct 2, 2017.
62. Hooper D, Coughlan J, Mullen M. Structural equation modelling: Guidelines for determining model fit. Articles. 2008:2.
63. Abdin E, Chong SA, Peh CX, et al. The mediational role of physical activity, social contact and stroke on the association between age, education, employment and dementia in an Asian older adult population. BMC psychiatry. 2017;17(1):98.
64. Reichenheim ME, Moraes CL, Lopes CS, Lobato G. The role of intimate partner violence and other health-related social factors on postpartum common mental disorders: a survey-based structural equation modeling analysis. BMC public health. 2014;14:427.
65. Austin PC. An Introduction to Propensity Score Methods for Reducing the Effects of Confounding in Observational Studies. Multivariate behavioral research. 2011;46(3):399-424.
66. Kopf D, Frolich L. Risk of incident Alzheimer's disease in diabetic patients: a systematic review of prospective trials. Journal of Alzheimer's disease : JAD. 2009;16(4):677-685.
67. Vagelatos NT, Eslick GD. Type 2 diabetes as a risk factor for Alzheimer's disease: the confounders, interactions, and neuropathology associated with this relationship. Epidemiologic reviews. 2013;35:152-160.
68. Velayudhan L, Poppe M, Archer N, Proitsi P, Brown RG, Lovestone S. Risk of developing dementia in people with diabetes and mild cognitive impairment. The British journal of psychiatry : the journal of mental science. 2010;196(1):36-40.
69. Craft S, Peskind E, Schwartz MW, Schellenberg GD, Raskind M, Porte D, Jr. Cerebrospinal fluid and plasma insulin levels in Alzheimer's disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology. 1998;50(1):164-168.
70. Baker LD, Cross DJ, Minoshima S, Belongia D, Watson GS, Craft S. Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch Neurol. 2011;68(1):51-57.
71. Craft S, Asthana S, Cook DG, et al. Insulin dose-response effects on memory and plasma amyloid precursor protein in Alzheimer's disease: interactions with apolipoprotein E genotype. Psychoneuroendocrinology. 2003;28(6):809-822.
72. De Felice FG, Vieira MN, Bomfim TR, et al. Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(6):1971-1976.
73. health NIo. Higher brain glucose levels may mean more severe Alzheimer’s-NIH study shows connections between glucose metabolism, Alzheimer’s pathology, symptoms. 2017; https://www.nih.gov/news-events/news-releases/higher-brain-glucose-levels-may-mean-more-severe-alzheimers. Accessed November 6, 2017.
74. Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D. Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. Archives of general psychiatry. 2006;63(5):530-538.
75. 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. European psychiatry : the journal of the Association of European Psychiatrists. 2017;43:92-98.
76. Zufferey V, Donati A, Popp J, et al. Neuroticism, depression, and anxiety traits exacerbate the state of cognitive impairment and hippocampal vulnerability to Alzheimer's disease. Alzheimer's & dementia (Amsterdam, Netherlands). 2017;7:107-114.
77. Burke SL, Cadet T, Alcide A, O'Driscoll J, Maramaldi P. Psychosocial risk factors and Alzheimer's disease: the associative effect of depression, sleep disturbance, and anxiety. Aging & mental health. 2017:1-8.
78. Peelle JE, Wingfield A. The neural consequences of age-related hearing loss. Trends in neurosciences. 2016;39(7):486-497.
79. Gates GA, Anderson ML, McCurry SM, Feeney MP, Larson EB. Central auditory dysfunction as a harbinger of Alzheimer dementia. Archives of otolaryngology--head & neck surgery. 2011;137(4):390-395.
80. Gates GA, Beiser A, Rees TS, D'Agostino RB, Wolf PA. Central auditory dysfunction may precede the onset of clinical dementia in people with probable Alzheimer's disease. J Am Geriatr Soc. 2002;50(3):482-488.
81. Panza F, Solfrizzi V, Logroscino G. Age-related hearing impairment-a risk factor and frailty marker for dementia and AD. Nature reviews Neurology. 2015;11(3):166-175.
82. Leandri M, Cammisuli S, Cammarata S, et al. Balance features in Alzheimer's disease and amnestic mild cognitive impairment. Journal of Alzheimer's disease : JAD. 2009;16(1):113-120.
83. Previc FH. Vestibular loss as a contributor to Alzheimer's disease. Medical hypotheses. 2013;80(4):360-367.
84. Rub U, Stratmann K, Heinsen H, et al. The Brainstem Tau Cytoskeletal Pathology of Alzheimer's Disease: A Brief Historical Overview and Description of its Anatomical Distribution Pattern, Evolutional Features, Pathogenetic and Clinical Relevance. Current Alzheimer research. 2016;13(10):1178-1197.
85. Lee YK, Hou SW, Lee CC, Hsu CY, Huang YS, Su YC. Increased risk of dementia in patients with mild traumatic brain injury: a nationwide cohort study. PloS one. 2013;8(5):e62422.
86. Hayes JP, Logue MW, Sadeh N, et al. Mild traumatic brain injury is associated with reduced cortical thickness in those at risk for Alzheimer's disease. Brain : a journal of neurology. 2017;140(3):813-825.
87. Chang KH, Chung CJ, Lin CL, Sung FC, Wu TN, Kao CH. Increased risk of dementia in patients with osteoporosis: a population-based retrospective cohort analysis. Age (Dordrecht, Netherlands). 2014;36(2):967-975.
88. Chen YH, Lo RY. Alzheimer's disease and osteoporosis. Ci ji yi xue za zhi = Tzu-chi medical journal. 2017;29(3):138-142.
89. Zhou R, Zhou H, Rui L, Xu J. Bone loss and osteoporosis are associated with conversion from mild cognitive impairment to Alzheimer's disease. Current Alzheimer research. 2014;11(7):706-713.
90. Downey CL, Young A, Burton EF, et al. Dementia and osteoporosis in a geriatric population: Is there a common link? World journal of orthopedics. 2017;8(5):412-423.
91. Hebert LE, Weuve J, Scherr PA, Evans DA. Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology. 2013;80(19):1778-1783.
92. Pike CJ. Sex and the development of Alzheimer's disease. Journal of neuroscience research. 2017;95(1-2):671-680.
93. Singh-Manoux A, Dugravot A, Fournier A, et al. Trajectories of Depressive Symptoms Before Diagnosis of Dementia: A 28-Year Follow-up Study. JAMA psychiatry. 2017;74(7):712-718.
94. 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.
95. Smith PA. The tantalizing links between gut microbes and the brain. Nature. 2015;526(7573):312-314.
96. Foster JA, McVey Neufeld KA. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013;36(5):305-312.
97. Daulatzai MA. Chronic functional bowel syndrome enhances gut-brain axis dysfunction, neuroinflammation, cognitive impairment, and vulnerability to dementia. Neurochemical research. 2014;39(4):624-644.
98. Carabotti M, Scirocco A, Maselli MA, Severi C. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Annals of gastroenterology. 2015;28(2):203-209.
99. Powell N, Walker MM, Talley NJ. The mucosal immune system: master regulator of bidirectional gut-brain communications. Nature reviews Gastroenterology & hepatology. 2017;14(3):143-159.
100. Fung TC, Olson CA, Hsiao EY. Interactions between the microbiota, immune and nervous systems in health and disease. Nature neuroscience. 2017;20(2):145-155.
101. Bu XL, Yao XQ, Jiao SS, et al. A study on the association between infectious burden and Alzheimer's disease. European journal of neurology. 2015;22(12):1519-1525.
102. Hausteiner-Wiehle C, Henningsen P. Irritable bowel syndrome: relations with functional, mental, and somatoform disorders. World journal of gastroenterology. 2014;20(20):6024-6030.
103. Bouchoucha M, Hejnar M, Devroede G, Babba T, Bon C, Benamouzig R. Anxiety and depression as markers of multiplicity of sites of functional gastrointestinal disorders: a gender issue? Clinics and research in hepatology and gastroenterology. 2013;37(4):422-430.
104. Van Oudenhove L, Levy RL, Crowell MD, et al. Biopsychosocial Aspects of Functional Gastrointestinal Disorders: How Central and Environmental Processes Contribute to the Development and Expression of Functional Gastrointestinal Disorders. Gastroenterology. 2016;150(6):1355-1367.e1352.
105. Hartono JL, Mahadeva S, Goh KL. Anxiety and depression in various functional gastrointestinal disorders: do differences exist? Journal of digestive diseases. 2012;13(5):252-257.
106. Schneiderhan J, Master-Hunter T, Locke A. Targeting gut flora to treat and prevent disease. The Journal of family practice. 2016;65(1):34-38.
107. Eisenstein M. Microbiome: Bacterial broadband. Nature. 2016;533(7603):S104-106.
108. 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. Nature reviews Urology. 2017;14(3):153-163.
109. Lucieer F, Duijn S, Van Rompaey V, et al. Full Spectrum of Reported Symptoms of Bilateral Vestibulopathy Needs Further Investigation-A Systematic Review. Frontiers in neurology. 2018;9:352.
110. Lucieer F, Vonk P, Guinand N, Stokroos R, Kingma H, van de Berg R. Bilateral Vestibular Hypofunction: Insights in Etiologies, Clinical Subtypes, and Diagnostics. Frontiers in neurology. 2016;7:26.
111. Strupp M. Challenges in neuro-otology. Frontiers in neurology. 2010;1:121.
112. Wei EX, Oh ES, Harun A, Ehrenburg M, Agrawal Y. Vestibular Loss Predicts Poorer Spatial Cognition in Patients with Alzheimer's Disease. Journal of Alzheimer's disease : JAD. 2018;61(3):995-1003.
113. Kim JY, Lee JW, Kim M, Kim MJ, Kim DK. Association of Idiopathic Sudden Sensorineural Hearing Loss With Affective Disorders. JAMA otolaryngology-- head & neck surgery. 2018;144(7):614-621.
114. Cosh S, Carriere I, Daien V, Tzourio C, Delcourt C, Helmer C. Sensory loss and suicide ideation in older adults: findings from the Three-City cohort study. International psychogeriatrics. 2018:1-7.
115. Soto-Perez-de-Celis E, Sun CL, Tew WP, et al. Association between patient-reported hearing and visual impairments and functional, psychological, and cognitive status among older adults with cancer. Cancer. 2018;124(15):3249-3256.
116. Smith L, Wilkinson D, Bodani M, Bicknell R, Surenthiran SS. Short-term memory impairment in vestibular patients can arise independently of psychiatric impairment, fatigue, and sleeplessness. Journal of neuropsychology. 2018.
117. Wang J, Tan L, Wang HF, et al. Anti-inflammatory drugs and risk of Alzheimer's disease: an updated systematic review and meta-analysis. Journal of Alzheimer's disease : JAD. 2015;44(2):385-396.
118. Malkki H. Alzheimer disease: NSAIDs protect neurons and preserve memory in a mouse model of AD. Nature reviews Neurology. 2016;12(7):370-371.
119. Ford AH, Hankey GJ, Yeap BB, Golledge J, Flicker L, Almeida OP. Hearing loss and the risk of dementia in later life. Maturitas. 2018;112:1-11.
120. Martini A, Castiglione A, Bovo R, Vallesi A, Gabelli C. Aging, cognitive load, dementia and hearing loss. Audiology & neuro-otology. 2014;19 Suppl 1:2-5.
121. Campbell J, Sharma A. Compensatory changes in cortical resource allocation in adults with hearing loss. Frontiers in systems neuroscience. 2013;7:71.
122. Ronnberg J, Rudner M, Lunner T, Zekveld AA. When cognition kicks in: working memory and speech understanding in noise. Noise & health. 2010;12(49):263-269.
123. 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):1534-1542.
124. Lin FR, Yaffe K, Xia J, et al. Hearing loss and cognitive decline in older adults. JAMA internal medicine. 2013;173(4):293-299.
125. Puschmann S, Thiel CM. Changed crossmodal functional connectivity in older adults with hearing loss. Cortex; a journal devoted to the study of the nervous system and behavior. 2017;86:109-122.
126. Lin FR, Ferrucci L, An Y, et al. Association of hearing impairment with brain volume changes in older adults. NeuroImage. 2014;90:84-92.
127. Rosemann S, Thiel CM. Audio-visual speech processing in age-related hearing loss: Stronger integration and increased frontal lobe recruitment. NeuroImage. 2018;175:425-437.
128. Guthrie DM, Davidson JGS, Williams N, 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.
129. 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 and hearing. 2018.
130. Dawes P, Emsley R, Cruickshanks KJ, et al. Hearing loss and cognition: the role of hearing AIDS, social isolation and depression. PloS one. 2015;10(3):e0119616.
131. Hsiao YH, Chang CH, Gean PW. Impact of social relationships on Alzheimer's memory impairment: mechanistic studies. Journal of biomedical science. 2018;25(1):3.
132. Maharani A, Dawes P, Nazroo J, Tampubolon G, Pendleton N. Longitudinal Relationship Between Hearing Aid Use and Cognitive Function in Older Americans. J Am Geriatr Soc. 2018.
133. Stern D, Hilly O. The relationship between hearing loss and cognitive dececline in the elderly and the efficiency of hearing rehabilitation in preventing cognitive decline. Harefuah. 2018;157(6):374-377.
134. Chaaya M, Phung K, Atweh S, et al. Socio-demographic and cardiovascular disease risk factors associated with dementia: Results of a cross-sectional study from Lebanon. Preventive medicine reports. 2018;9:1-5.
135. Lundgaard I, Wang W, Eberhardt A, et al. Beneficial effects of low alcohol exposure, but adverse effects of high alcohol intake on glymphatic function. Scientific reports. 2018;8(1):2246.
136. Pfefferbaum A, Lim KO, Zipursky RB, et al. Brain gray and white matter volume loss accelerates with aging in chronic alcoholics: a quantitative MRI study. Alcoholism, clinical and experimental research. 1992;16(6):1078-1089.
137. Schwarzinger M, Thiebaut SP, Baillot S, Mallet V, Rehm J. Alcohol use disorders and associated chronic disease - a national retrospective cohort study from France. BMC public health. 2017;18(1):43.
138. Langballe EM, Ask H, Holmen J, et al. Alcohol consumption and risk of dementia up to 27 years later in a large, population-based sample: the HUNT study, Norway. European journal of epidemiology. 2015;30(9):1049-1056.
139. Hung SC, Liao KF, Muo CH, Lai SW, Chang CW, Hung HC. Hearing Loss is Associated With Risk of Alzheimer's Disease: A Case-Control Study in Older People. Journal of epidemiology. 2015;25(8):517-521.