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Cited by 40Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchInflammatory mediators and NSAID effects

Diclofenac reduces the risk of Alzheimer’s disease: a pilot analysis of NSAIDs in two US veteran populations

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Stuve, Olaf, Weideman, Rick A., McMahan, Danni M., Jacob, David A., Little, Bertis B.·2020·Therapeutic Advances in Neurological Disorders
DOI 10.1177/1756286420935676PMC PMC7325551
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Abstract

Background: Our aim was to determine whether specific nonsteroidal anti-inflammatory (NSAID) agents are associated with a decreased frequency of Alzheimer’s disease (AD). Materials and methods: Days of drug exposure were determined for diclofenac, etodolac, and naproxen using US Department of Veterans Affairs (VA) pharmacy transaction records, combined from two separate VA sites. AD diagnosis was established by the International Classification of Diseases, ninth revision (ICD-9)/ICD-10 diagnostic codes and the use of AD medications. Cox regression survival analysis was used to evaluate the association between AD frequency and NSAID exposure over time. Age at the end of the study and the medication-based disease burden index (a comorbidity index) were used as covariates. Results: Frequency of AD was significantly lower in the diclofenac group (4/1431, 0.28%) compared with etodolac (328/14,646, 2.24%), and naproxen (202/12,203, 1.66%). For regression analyses, naproxen was chosen as the comparator drug, since it has been shown to have no effect on the development of AD. Compared with naproxen, etodolac had no effect on the development of AD, hazard ratio (HR) 1.00 [95% confidence interval (CI): 0.84–1.20, p = 0.95]. In contrast, diclofenac had a significantly lower HR of AD compared with naproxen, HR 0.25 (95% CI: 0.09–0.68, p <0.01). After site effects were controlled for, age at end of the study (HR = 1.08, 95% CI: 1.07–1.09, p <0.001) was also found to influence the development of AD, and the medication-based disease burden index was a strong predictor for AD, HR 5.17 (95% CI: 4.60–5.81) indicating that as comorbidities increase, the risk for AD increases very significantly. Conclusion: Diclofenac, which has been shown to have active transport into the central nervous system, and which has been shown to lower amyloid beta and interleukin 1 beta, is associated with a significantly lower frequency of AD compared with etodolac and naproxen. These results are compelling, and parallel animal studies of the closely related fenamate NSAID drug class.

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  1. [1]Mendiola-Precoma J Berumen LC Padilla K, et al Therapies for prevention and treatment of Alzheimer’s disease. Biomed Res Int 2016; 2016: 2589276. 27547756 PMC4980501
  2. [2]Kidd M. Alzheimer’s disease–an electron microscopical study. Brain 1964; 87: 307– 320. 14188276
  3. [3]Terry RD Gonatas NK Weiss M. Ultrastructural studies in Alzheimer’s presenile dementia. Am J Pathol 1964; 44: 269– 297. 14119171 PMC1906996
  4. [4]Dresse A Marechal D Scuvee-Moreau J, et al Towards a pharmacological approach of Alzheimer’s disease based on the molecular biology of the amyloid precursor protein (App). Life Sci 1994; 55: 2179– 2187. 7997077
  5. [5]Kosik KS Joachim CL Selkoe DJ. Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc Natl Acad Sci U S A 1986; 83: 4044– 4048. 2424016 PMC323662
  6. [6]Nukina N Ihara Y. One of the antigenic determinants of paired helical filaments is related to tau protein. J Biochem 1986; 99: 1541– 1544. 2423512
  7. [7]Pollock NJ Mirra SS Binder LI, et al Filamentous aggregates in pick’s disease, progressive supranuclear palsy, and Alzheimer’s disease share antigenic determinants with microtubule-associated protein, tau. Lancet 1986; 2: 1211. 2430155
  8. [8]Wolozin BL Pruchnicki A Dickson DW, et al A neuronal antigen in the brains of Alzheimer patients. Science 1986; 232: 648– 650. 3083509
  9. [9]Wood JG Mirra SS Pollock NJ, et al (1986) Neurofibrillary tangles of Alzheimer Disease share antigenic determinants with the axonal microtubule-associated protein tau (tau). Proc Natl Acad Sci USA 1986; 83: 4040– 4043. 2424015 PMC323661
  10. [10]Davies P Maloney AJ. Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet 1976; 2: 1403. 63862
  11. [11]White P Hiley CR Goodhardt MJ, et al Neocortical cholinergic neurons in elderly people. Lancet 1977; 1: 668– 671. 66473
  12. [12]Wang WY Tan MS Yu JT, et al Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Ann Transl Med 2015; 3: 136. 26207229 PMC4486922
  13. [13]Rozemuller JM Eikelenboom P Stam FC. Role of microglia in plaque formation in senile dementia of the Alzheimer type. An immunohistochemical study. Virchows Arch B Cell Pathol Incl Mol Pathol 1986; 51: 247– 254. 2874657
  14. [15]Rogers J Luber-Narod J Styren SD, et al Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer’s disease. Neurobiol Aging 1988; 9: 339– 349. 3263583
  15. [17]Cacabelos R Barquero M Garcia P, et al Cerebrospinal fluid interleukin-1 beta (IL-1 beta) in Alzheimer’s Disease and neurological disorders. Methods Find Exp Clin Pharmacol 1991; 13: 455– 458. 1784142
  16. [18]Abderrazak A Syrovets T Couchie D, et al NLRP3 inflammasome: from a danger signal sensor to a regulatory node of oxidative stress and inflammatory diseases. Redox Biol 2015; 4: 296– 307. 25625584 PMC4315937
  17. [19]Griffin WS Stanley LC Ling C, et al Brain interleukin 1 and S-100 immunoreactivity are elevated in down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A 1989; 86: 7611– 7615. 2529544 PMC298116
  18. [20]Donnelly RJ Friedhoff AJ Beer B, et al Interleukin-1 stimulates the beta-amyloid precursor protein promoter. Cell Mol Neurobiol 1990; 10: 485– 495. 2091832 PMC11567380
  19. [21]Tilleux S Hermans E. Neuroinflammation and regulation of glial glutamate uptake in neurological disorders. J Neurosci Res 2007; 85: 2059– 2070. 17497670
  20. [22]Gray CW Patel AJ. Regulation of beta-amyloid precursor protein isoform mRNAs by transforming growth factor-beta 1 and interleukin-1 beta in astrocytes. Brain Res Mol Brain Res 1993; 19: 251– 256. 8412571
  21. [23]Griffin WS Sheng JG Roberts GW, et al Interleukin-1 expression in different plaque types in Alzheimer’s disease: significance in plaque evolution. J Neuropathol Exp Neurol 1995; 54: 276– 281. 7876895
  22. [24]Vawter MP Basaric-Keys J Li Y, et al Human olfactory neuroepithelial cells: tyrosine phosphorylation and process extension are increased by the combination of IL-1beta, IL-6, NGF, and bFGF. Exp Neurol 1996; 142: 179– 194. 8912909
  23. [25]Sheng JG Zhu SG Jones RA, et al Interleukin-1 promotes expression and phosphorylation of neurofilament and tau proteins in vivo. Exp Neurol 2000; 163: 388– 391. 10833312 PMC3886634
  24. [26]Li Y Liu L Barger SW, et al Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. J Neurosci 2003; 23: 1605– 1611. 12629164 PMC3833596
  25. [27]Jaturapatporn D Isaac MG Mccleery J, et al Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer’s disease. Cochrane Database Syst Rev 2012; 15: CD006378. PMC11337172 22336816
  26. [29]Rogers J Kirby LC Hempelman SR, et al Clinical trial of indomethacin in Alzheimer’s disease. Neurology 1993; 43: 1609– 1611. 8351023
  27. [30]De Jong D Jansen R Hoefnagels W, et al No effect of one-year treatment with indomethacin on Alzheimer’s disease progression: a randomized controlled trial. PLoS One 2008; 3: e1475. 18213383 PMC2194921
  28. [31]Soininen H West C Robbins J, et al Long-term efficacy and safety of celecoxib in Alzheimer’s disease. Dement Geriatr Cogn Disord 2007; 23: 8– 21. 17068392
  29. [32]Aisen PS Schafer KA Grundman M, et al Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA 2003; 289: 2819– 2826. 12783912
  30. [33]ADAPT-FS Research Group. Follow-up evaluation of cognitive function in the randomized Alzheimer’s disease anti-inflammatory prevention trial and its follow-up study. Alzheimers Dement 2015; 11: 216– 225 e1. 25022541 PMC4287453
  31. [34]Meyer PF Tremblay-Mercier J Leoutsakos J, et al INTREPAD: a randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease. Neurology 2019; 92: e2070– e2080. 30952794 PMC6512884
  32. [35]Breitner J Meyer PF Author response: INTREPAD: a randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease. Neurology 2020; 94: 594. 32229636
  33. [37]Zhang C Wang Y Wang D, et al NSAID exposure and risk of Alzheimer’s disease: an updated meta-analysis from cohort studies. Front Aging Neurosci 2018; 10: 83. 29643804 PMC5882872
  34. [38]Kastrup EK. Drug facts and comparisons. St. Louis, Missouri: Wolters Kluwer Health, 2017; 2070.
  35. [39]Joo Y Kim HS Woo RS, et al Mefenamic acid shows neuroprotective effects and improves cognitive impairment in in vitro and in vivo Alzheimer’s disease models. Mol Pharmacol 2006; 69: 76– 84. 16223958
  36. [40]Daniels MJ Rivers-Auty J Schilling T, et al Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models. Nat Commun 2016; 7: 12504. 27509875 PMC4987536
  37. [41]Duff K Eckman C Zehr C, et al Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 1996; 383: 710– 713. 8878479
  38. [42]Lewis J Dickson DW Lin WL, et al Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 2001; 293: 1487– 1491. 11520987
  39. [43]Terwel D Lasrado R Snauwaert J, et al Changed conformation of mutant Tau-P301l underlies the moribund tauopathy, absent in progressive, nonlethal axonopathy of Tau-4R/2N transgenic mice. J Biol Chem 2005; 280: 3963– 3973. 15509565
  40. [44]Hussain RZ Miller-Little WA Lambracht-Washington D, et al Laquinimod has no effects on brain volume or cellular CNS composition in the F1 3xTg-AD/C3H mouse model of Alzheimer’s disease. J Neuroimmunol 2017; 309: 100– 110. 28601278 PMC7169431
  41. [45]Rivers-Auty JM Mather AE Peters R, et al (2018) Use of common pain relieving drugs correlate with altered progression of Alzheimer’s disease and mild cognitive impairment. Alzheimer’s Association International Conference, Chicago, IL.
  42. [46]George J Vuong T Bailey MJ, et al Development and validation of the medication-based disease burden index. Ann Pharmacother 2006; 40: 645– 650. 16569815
  43. [47]Fukuda M Kitaichi K Abe F, et al Altered brain penetration of diclofenac and mefenamic acid, but not acetaminophen, in Shiga-like toxin II-treated mice. J Pharmacol Sci 2005; 97: 525– 532. 15821337
  44. [48]Zecca L Ferrario P Costi P. Determination of diclofenac and its metabolites in plasma and cerebrospinal fluid by high-performance liquid chromatography with electrochemical detection. J Chromatogr 1991; 567: 425– 432. 1939474
  45. [49]Kokki H Kumpulainen E Laisalmi M, et al Diclofenac readily penetrates the cerebrospinal fluid in children. Br J Clin Pharmacol 2008; 65: 879– 884. 18477264 PMC2485236
  46. [50]Scharf S Mander A Ugoni A, et al A double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer’s disease. Neurology 1999; 53: 197– 201. 10408559

Cited by

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Authors
Stuve, O., Weideman, R. A., McMahan, D. M., Jacob, D. A., & Little, B. B.
Affiliations
  • Department of Neurology and Neurotherapeutics, University of Texas, Southwestern Medical School, Neurology Section (111H), Dallas VA Medical Center, 4500 Lancaster Road, Dallas, TX 75216, USA
  • Dallas VA Medical Center (US)
  • VA Heart of Texas Health Care Network (US)
  • University of Louisville (US)
ORCID
Venue
Therapeutic Advances in Neurological Disorders
Publisher
SAGE Publications
Published
2020-01
Volume
13
Pages
1756286420935676-1756286420935676
ISSN
  • 1756-2856 (ISSN-L)
  • 1756-2864
DOI
10.1177/1756286420935676
PMC
PMC7325551
OpenAlex
W3037059823
Cited by
40
References
5
Citations by year
2026: 2 · 2025: 5 · 2024: 8 · 2023: 10 · 2022: 8 · 2021: 7
FWCI
3.76
Type
journal article
Language
en
Open access
Licence
Locations
  • Therapeutic Advances in Neurological Disorders (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
Keywords
Alzheimer's disease, diclofenac, nonsteroidal anti-inflammatory drugs, etodolac, naproxen, drug exposure, veterans, comorbidities, amyloid-beta, IL-1β, disease risk reduction, drug repurposing, Department of Veterans Affairs

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