Explore the Risk and Protect Factor for the Dementia of Late-Onset Alzheimer's Disease (LOAD) by Data Mining Technology

Autor: Liu, Chin-Mei, 劉瀞鎂
Rok vydání: 2019
Druh dokumentu: 學位論文 ; thesis
Popis: 107
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.
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