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Ijcem0092463.Pdf Int J Clin Exp Med 2019;12(8):10197-10206 www.ijcem.com /ISSN:1940-5901/IJCEM0092463 Original Article The relationship between nonsteroidal anti-inflammatory drug use and the risk of Alzheimer’s disease: an updated meta-analysis of cohort studies Shi-Liang Ji1, Xing-Xing Zhao2, Ting Fu3, Yan-Li Liu4, Cheng Wang1 1Department of Pharmacy, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou 215153, P. R. China; 2Department of Neonatology, Suzhou Municipal Hospital, Suzhou 215025, P. R. China; 3Department of Anesthesiology and Perioperative Medicine, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou 215153, P. R. China; 4College of Pharmaceutical Science, Soochow University, Suzhou 215123, P. R. China Received February 12, 2019; Accepted May 10, 2019; Epub August 15, 2019; Published August 30, 2019 Abstract: Aim of the study: We aimed to evaluate the potential relevance between nonsteroidal anti-inflammatory drug (NSAIDs) use and the risk of Alzheimer’s disease (AD). Clinical rationale for the study: Previous studies and systematic reviews have suggested that the use of NSAIDs might be associated with a reduced incidence of AD. However, several studies do not corroborate these results. Materials and Methods: PubMed, Embase, and Cochrane library databases were searched up until May 8th, 2018. Adjusted relative risks (RRs) and 95% confidence intervals (CIs) were calculated and combined with random-effects models. Results: A total of 14 cohort studies with 81571 participants were included in the final meta-analysis. Overall, the results of this meta-analysis indicated that the use of all NSAIDs (RR = 0.88, 95% CI = 0.74-1.05) and aspirin (RR = 0.99, 95% CI = 0.82-1.20) or non-aspirin NSAIDs re- vealed no significant effect on AD risk. However, our study showed that aspirin might decrease the risk of dementia overall (RR = 1.22, 95% CI = 1.02-1.45); there was no significant risk of dementia observed in users of all NSAIDs (RR = 0.99, 95% CI = 0.83-1.18) or non-aspirin NSAIDs (RR = 0.97, 95% CI = 0.70-1.35). In the subgroup analyses, a significant association was observed between aspirin use and the risk of dementia during a short follow-up period (RR = 1.46, 95% CI = 1.16-1.84, P = 0.001). Conclusion: NSAIDs are not associated with the excess risk of AD inci- dence. But aspirin may reduce the risk of other types of dementia other than AD. Keywords: Non-steroidal anti-inflammatory drugs, Alzheimer’s disease, dementia, meta-analysis Introduction substantial evidence has indicated that non- steroidal anti-inflammatory drugs (NSAIDs) mi- Dementia is a devastating disease, which is ght protect against the development of AD [5]. characterized by a loss of abilities related to However, other studies showed that there was thinking, emotions and behavior. Dementia can no effect of NSAIDs on preventing the develop- be classified into four major types, including ment of AD [6]. The reverse findings may be a Alzheimer’s disease (AD), vascular dementia, result of a limited sample size [7]. Therefore, we Lewy body dementia, and frontotemporal de- performed this updated meta-analysis to ana- mentia [1]. AD is the most common type of de- lyze the association between AD and NSAID mentia, accounting for 60%-70% of all demen- use. Compared with previous meta-analyses, tias [2]. It is indicated that AD affected about this study included newly published papers and 29.8 million people worldwide in 2015 [3] and numerous subgroup analyses. most of the patients are over 65 years old [2]. AD poses a serious threat to people’s health In this paper, we conducted an updated meta- [4]. analysis of 14 studies to reevaluate the associ- ation between NSAID use and the risk of AD. It is reported that neuro-inflammation plays a The influence of the long-term effect and popu- key role in the pathogenesis of AD. Recently, lations were further analyzed. The risk of NSAID for Alzheimer’s disease were adults without demen- tia or Alzheimer’s disease; 3) studies that presented data on the adjusted HR (hazard ratio), relative risk (RR) or odds ratio (OR) and 95% confidence interval (CI). The exclusion criteria are li- sted as follows: 1) studies which include family mem- bers or close relatives; 2) literatures which are revi- ews, comments or letters; 3) the redundant publica- tions or multiple studies with the same data. Figure 1. Flow chat of literature Data extraction and meth- search and study selection. odology quality assess- ment Methods All the pertinent articles were reviewed by two independent investigators according to the Search strategy for included studies inclusion and exclusion criteria. Data extraction was performed by two investigators indepen- This meta-analysis was conducted in accor- dently, including the first author, publication dance with PRISMA guidelines [8]. Two authors year, research region, basic information of sub- (SLJ and TF) performed an independent and jects, sample size, the type of diseases and extensive literature search in PubMed, EMB- NSAID used, et al. Data were used in the meta- ASE, and Cochrane library from their beginning analysis, if there was a common consensus till August 8th, 2017. The following keywords, viewpoint. The quality of the included studies “Alzheimer Disease”, “Alzheimer*”, “dement*”, was appraised according to the Newcastle- “Anti-Inflammatory Agents, Non-Steroidal”, “NS- Ottawa Scale (NOS) [9]. Three items were AIDs”, and “non-steroidal anti-inflammatory dr- scored as follows: object selection (4 scores), ug*”, were used to search eligible articles. The comparability (2 scores) and exposure (3 sco- search strategies against different libraries are res). shown in Table S1. Statistical analysis All potentially relevant studies were retrieved and evaluated for study eligibility. Manual se- The association between NSAID use and risk of arch techniques were also used to identify AD was evaluated with RRs and 95% CIs. other potentially relevant studies. All analyses Cochran’s Q statistic and I2 test were used to were based on previously published studies, test heterogeneity between studies [10]. A Q thus no ethical approval and patient consent statistic P<0.05 and/or I2>50% indicated het- are required. erogeneity between studies, thus we used ran- dom effect model to evaluate the pooled effect Study inclusion criteria of outcomes. Otherwise, when P≥0.05 and I2≤50%, a fix-effect method was applied. Sub- Cohort studies were included if they met the fol- group analysis was conducted based on differ- lowing criteria: 1) studies that compared the ent populations and follow-up periods. We used risk of AD or other types of dementia in patients the method through visual inspection of the exposed to NSAIDs (aspirin and non-aspirin funnel plot symmetry, Egger’s test and Begg’s NSAIDs) and those that never reviewed NSAID test were implemented to detect between- use; 2) studies where the enrolled subjects study publication bias, in which P<0.05 indicat- 10198 Int J Clin Exp Med 2019;12(8):10197-10206 The risk of NSAID for Alzheimer’s disease Table 1. Characteristics of prospective cohort studies of nonsteroidal anti-inflammatory drug and Alzheimer’s disease Risk included in a Meta- anaylsis Type of Population Follow-up, Authors n, Age, years Sex NSAID type Adjusted variables dementia origin years Ancelin, ML 2012, France Dementia, Community 7 7234, 73.7 (5.2) M, F All NSAID Gender, center, age, education, depression, ischemic pathologies, AD diabetes, hypercholesterolemia, caffeine, smoking, APOE 4, chronic joint or back pain, chronic bronchitis, asthma, and other chronic respiratory disorders Arvanitakis, Z 2008, USA AD Older Catholic 12 1019, 75 M&F Non-aspirin NSAIDs, Aspirin Age, sex, and education clergy Breitner, JC 2009, USA Dementia, Community 12 2736, 74.8 M&F All NSAID Age, sex, APOE status, education, underlying diseases, body mass AD index, and regular exercise Chang, CW 2016, Taiwan Dementia, T2DM 5 13596, 66.9 M&F Aspirin Age, gender, CCI, stroke types, antidiabetic drugs, statins, and AD (7.9)/64.8 (8.2) hypertensive drugs Chang, KH 2016, Taiwan Dementia RA 6.7 33229, 53.9 (14.2) M&F All NSAID Age, diabetes, hypertension, hyperlipidemia, coronary artery disease, head injury, stroke, COPD, congestive heart failure, and depression Cornelius, C 2004, Sweden Dementia, Community 10 1031, ≥75 M&F All NSAID (Aspirin, Age, gender, education and underlying diseases AD non-aspirin NSAIDs) Cote, S 2012, Canada Dementia, Community 10 5276, 75.5 (6.5) M&F All NSAID, non-aspirin Gender, education, smoking, alcohol, antioxidant vitamin use, physi- AD NSAIDs cal activity, arthritis, migraines, comorbidity, and vascular risk factors Fourrier, A 1996, France Dementia Community 3 1252, ≥65 M&F All NSAID NR Fischer, P 2008, Austria AD Community 2.5 479, ≥75 M&F All NSAID NR Henderson, AS 1997, Australia Dementia Community 3.6 588, 80.3 (5.0) M&F Aspirin, non-aspirin NSAIDs Age, sex, education, stroke, APOE gene, arthritis medication In t’ Veld, BA 2001, the Netherlands AD Community 6.8 6989, ≥55 M&F Non-aspirin NSAIDs, Aspirin Age, sex, education, smoking, and concomitant medication Stewart, WF 1997, USA AD Volunteers 16 1686, ≥65 M&F Aspirin, non-aspirin NSAIDs Age, sex, education, calendar year of follow-up Szekely, CA 2008, USA Dementia Community 10 3229, ≥65 M&F Aspirin, non-aspirin NSAIDs Age, sex, education level, presence of APOE 4, race (white or African American), and baseline 3MSE. Zandi, PP 2002, USA AD Community 3 3227, ≥65 M&F Aspirin, non-aspirin NSAIDs Age, sex, education, APOE gene AD = Alzheimer’s disease; RA = Rheumatoid arthritis; T2DM = Type 2 diabetes mellitus; M = male; F = female; NR = not reported. 10199 Int J Clin Exp Med 2019;12(8):10197-10206 The risk of NSAID for Alzheimer’s disease Table 2.
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