Anti-inflammatories in Alzheimer’s disease—potential therapy or spurious correlate?
Open accessAbstract
Epidemiological evidence suggests non-steroidal anti-inflammatory drugs reduce the risk of Alzheimer’s disease. However, clinical trials have found no evidence of non-steroidal anti-inflammatory drug efficacy. This incongruence may be due to the wrong non-steroidal anti-inflammatory drugs being tested in robust clinical trials or the epidemiological findings being caused by confounding factors. Therefore, this study used logistic regression and the innovative approach of negative binomial generalized linear mixed modelling to investigate both prevalence and cognitive decline, respectively, in the Alzheimer’s Disease Neuroimaging dataset for each commonly used non-steroidal anti-inflammatory drug and paracetamol. Use of most non-steroidal anti-inflammatories was associated with reduced Alzheimer’s disease prevalence yet no effect on cognitive decline was observed. Paracetamol had a similar effect on prevalence to these non-steroidal anti-inflammatory drugs suggesting this association is independent of the anti-inflammatory effects and that previous results may be due to spurious associations. Interestingly, diclofenac use was significantly associated with both reduce incidence and slower cognitive decline warranting further research into the potential therapeutic effects of diclofenac in Alzheimer’s disease.
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Epidemiological data suggest NSAIDs are associated with increased risk for AD.
“Epidemiological data have suggested that NSAIDs are associated with increased risk for AD, but multiple clinical trials have failed to bear that out.541”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [541]
The Introduction says numerous epidemiological studies associated NSAID use with a lower, not increased, risk of developing Alzheimer disease. It also reports that several clinical trials found no significant effect on disease progression, so the trial portion of the citing sentence is supported, but its account of the epidemiological evidence is reversed. (LLM, conf=0.94)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredMultiple clinical trials failed to confirm the association between NSAIDs and increased risk for AD.
“but multiple clinical trials have failed to bear that out.541”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [541]
The Introduction (page not specified) says epidemiological studies associated NSAID use with a lower, not increased, risk of developing Alzheimer’s disease. It reports that multiple clinical trials found no significant effect on disease progression; those trials did not test the claimed increased-risk association. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredEpidemiological evidence suggests that non-steroidal anti-inflammatory drugs may reduce the risk of AD, but the majority of NSAIDs fail to reduce the prevalence of AD or influence the progression of AD-associated cognitive decline.
“Although epidemiological evidence suggest that non-steroidal anti-inflammatory drugs may reduce the risk of AD, the majority of NSAIDs fail to reduce the prevalence of AD or influence the progression of AD-associated cognitive decline (Rivers-Auty et al. 2020).”
From Perineuronal net deglycosylation associates with tauopathy‐induced gliosis and neurodegeneration (2024) · cites this paper as Rivers-Auty et al. 2020
The Introduction reports epidemiological evidence associating NSAID use with a lower risk of developing Alzheimer’s disease. It also says the study examined cognitive decline rather than incidence or prevalence; the Results found no significant change in cognitive decline for most NSAIDs studied. The claim that most NSAIDs fail to reduce Alzheimer’s disease prevalence is therefore not established by this paper. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDiclofenac remains the only NSAID associated with slower cognitive decline, likely through COX-independent mechanisms.
“Diclofenac remains the only NSAID associated with slower cognitive decline, although likely through cytochrome c oxidase (COX)-independent mechanisms [94].”
From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [94]
The Results section reports that diclofenac was the only NSAID associated with reduced cognitive decline, and the Conclusion suggests its potential effect is independent of COX inhibition. But the Introduction explicitly defines COX as cyclooxygenase, not cytochrome c oxidase as the citing sentence states. The proposed mechanism is a hypothesis, not an established finding. (LLM, conf=0.92)
Experimental — accuracy not yet measuredClinical trials of NSAIDs in MCI and established AD have yielded largely negative results.
“While epidemiological studies suggested that chronic non-steroidal anti-inflammatory drug (NSAID) use might lower AD risk, clinical trials in MCI and established AD have yielded largely negative results.”
From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [94]
The Introduction (page unavailable) reports that several NSAID trials found no significant effect on Alzheimer’s disease progression, supporting the claim about established AD. The paper also studies people with MCI, but that analysis uses a longitudinal dataset rather than clinical trials; the cited passages do not establish negative trial results in MCI. (LLM, conf=0.86)
Experimental — accuracy not yet measured
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Cites
NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice
Heneka, M. T., Kummer, M. P., Stutz, A., Delekate, A., Schwartz, S., Vieira-Saecker, A., Griep, A., Axt, D., Remus, A., Tzeng, T.-C., et al. (2013) · Nature · doi:10.1038/nature11729 · Cited by 2,898 · see citing works
Innate Immune Activation Through Nalp3 Inflammasome Sensing of Asbestos and Silica
Dostert, C., Pétrilli, V., Van Bruggen, R., Steele, C., Mossman, B. T., & Tschopp, J. (2008) · Science · doi:10.1126/science.1156995 · Cited by 2,658 · see citing works
A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity
Weggen, S., Eriksen, J. L., Das, P., Sagi, S. A., Wang, R., Pietrzik, C. U., Findlay, K. A., Smith, T. E., Murphy, M. P., Bulter, T., et al. (2001) · Nature · doi:10.1038/35102591 · Cited by 1,388 · see citing works
Nonsteroidal Antiinflammatory Drugs and the Risk of Alzheimer's Disease
in 't Veld, B. A., Ruitenberg, A., Hofman, A., Launer, L. J., van Duijn, C. M., Stijnen, T., Breteler, M. M. B., & Stricker, B. H. C. (2001) · New England Journal of Medicine · doi:10.1056/nejmoa010178 · Cited by 1,196 · see citing works
Risk of Alzheimer's disease and duration of NSAID use
Stewart, W. F., Kawas, C., Corrada, M., & Metter, E. J. (1997) · Neurology · doi:10.1212/wnl.48.3.626 · Cited by 1,132 · see citing works
Protective effects of NSAIDs on the development of Alzheimer disease
Vlad, S. C., Miller, D. R., Kowall, N. W., & Felson, D. T. (2008) · Neurology · doi:10.1212/01.wnl.0000311269.57716.63 · Cited by 535 · see citing works
Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial
ADAPT Research Group (2007) · Neurology · doi:10.1212/01.wnl.0000260269.93245.d2 · Cited by 354 · see citing works
Pasqualetti, P., Bonomini, C., Dal Forno, G., Paulon, L., Sinforiani, E., Marra, C., Zanetti, O., & Maria Rossini, P. (2009) · Aging Clinical and Experimental Research · doi:10.1007/bf03325217 · Cited by 172 · see citing works
Flagged first, then by citations
Research works printed but not linked: 39
- Alzheimers Association. Alzheimer's Association Report 2015 Alzheimer's disease facts and figures. Alzheimers Dement 2015; 11: 332– 84. 25984581
- Alzheimer's Disease Anti-Inflammatory Prevention Trial Research Group. Results of a follow-up study to the randomized Alzheimer's disease Anti-inflammatory Prevention Trial (ADAPT). Alzheimers Dement 2013; 9: 714– 23. 23562431 PMC3823756
- Bartzokis G Lu PH Geschwind DH Edwards N Mintz J Cummings JL. Apolipoprotein E genotype and age-related myelin breakdown in healthy individuals—implications for cognitive decline, and dementia. Arch Gen Psychiatry 2006; 63: 63– 72. 16389198
- Breitner JCS Welsh KA Helms MJ Gaskell PC Gau BA Roses AD, et al Delayed-onset of Alzheimers-disease with nonsteroidal antiinflammatory and histamine-H2 blocking-drugs. Neurobiol Aging 1995; 16: 523– 30. 8544901
- Conaghan PG. A turbulent decade for NSAIDs: update on current concepts of classification, epidemiology, comparative efficacy, and toxicity. Rheumatol Int 2012; 32: 1491– 502. 22193214 PMC3364420
- Cornelius C Fastbom J Winblad B Viitanen M. Aspirin, NSAIDs, risk of dementia, and influence of the apolipoprotein E epsilon 4 allele in an elderly population. Neuroepidemiology 2004; 23: 135– 43. 15084783
- Cote S Carmichael PH Verreault R Lindsay J Lefebvre J Laurin D. Nonsteroidal anti-inflammatory drug use and the risk of cognitive impairment and Alzheimer's disease. Alzheimers Dement 2012; 8: 219– 26. 22546354
- Daniels MJD Rivers-Auty J Schilling T Spencer NG Watremez W Fasolino V, et al Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models. Nat Commun 2016; 7: 12504. 27509875 PMC4987536
- Dempsey C Rubio Araiz A Bryson KJ Finucane O Larkin C Mills EL, et al Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-beta and cognitive function in APP/PS1 mice. Brain Behav Immun 2017; 61: 306– 16. 28003153
- Fischer P Zehetmayer S Jungwirth S Weissgram S Krampla W Hinterberger M, et al Risk factors for Alzheimer dementia in a community-based birth cohort at the age of 75 years. Dement Geriatr Cogn Disord 2008; 25: 501– 7. 18446027
- Fournier D Skaug H Ancheta J Ianelli J Magnusson A Maunder M, et al AD Model Builder: using automatic differentiation for statistical inference of highly parameterized complex nonlinear models. Optim Methods Softw 2012; 27: 233– 49.
- Hardin JW Hilbe JM Hilbe J. Generalized linear models and extensions. Texas: Stata Press; 2007.
- Hosmer JDW Lemeshow S Model-building strategies and methods for logistic regression In: Shewhart WA, Wilks SS, Hosmer DW, Lemeshow S, editors. Applied logistic regression. Chap. 4. Hoboken, New Jersey: John Wiley & Sons, Inc; 2005 p. 89– 151.
- Imbimbo BP Solfrizzi V Panza F. Are NSAIDs useful to treat Alzheimer's disease or mild cognitive impairment? Front Aging Neurosci 2010; 2: 19. PMC2912027 20725517
- Kanai M Shizuka M Urakami K Matsubara E Harigaya Y Okamoto K, et al Apolipoprotein E4 accelerates dementia and increases cerebrospinal fluid tau levels in Alzheimer's disease. Neurosci Lett 1999; 267: 65– 8. 10400250
- Kim YJ Seo SW Park SB Yang JJ Lee JS Lee J, et al Protective effects of ApoE e2 against disease progression in subcortical vascular mild cognitive impairment patients: a three-year longitudinal study. Sci Rep 2017; 7: 1910. 28507298 PMC5432504
- Klinger-Gratz PP Ralvenius WT Neumann E Kato A Nyilas R Lele Z, et al Acetaminophen relieves inflammatory pain through CB1 cannabinoid receptors in the rostral ventromedial medulla. J Neurosci 2018; 38: 322. 29167401 PMC6596108
- Landi F Cesari M Onder G Russo A Torre S Bernabei R. Non-steroidal anti-inflammatory drug (NSAID) use and Alzheimer disease in community-dwelling elderly patients. Am J Geriatr Psychiatry 2003; 11: 179– 85. 12611747
- Lim GP Yang F Chu T Chen P Beech W Teter B, et al Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease. J Neurosci 2000; 20: 5709– 14. 10908610 PMC6772529
- Lo RY Hubbard AE Shaw LM Trojanowski JQ Petersen RC Aisen PS, et al Longitudinal change of biomarkers in cognitive decline. Arch Neurol 2011; 68: 1257– 66. 21670386 PMC5604752
- Mielke MM Leoutsakos J-M Tschanz JT Green RC Tripodis Y Corcoran CD, et al Interaction between vascular factors and the ApoE ε4 allele in predicting rate of progression in Alzheimer's disease. JAD 2011; 26: 127– 34. 21593560 PMC3164737
- Morra JH Tu Z Apostolova LG Green AE Avedissian C Madsen SK, et al Automated mapping of hippocampal atrophy in 1-year repeat MRI data from 490 subjects with Alzheimer's disease, mild cognitive impairment, and elderly controls. NeuroImage 2009; 45: S3– 15. 19041724 PMC2733354
- Notkola IL Sulkava R Pekkanen J Erkinjuntti T Ehnholm C Kivinen P, et al Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease. Neuroepidemiology 1998; 17: 14– 20. 9549720
- Rawle MJ Davis D Bendayan R Wong A Kuh D Richards M. Apolipoprotein-E (ApoE) ε4 and cognitive decline over the adult life course. Transl Psychiatry 2018; 8: 18. 29317609 PMC5802532
- Reines SA Block GA Morris JC Liu G Nessly ML Lines CR, et al Rofecoxib—no effect on Alzheimer's disease in a 1-year, randomized, blinded, controlled study. Neurology 2004; 62: 66– 71. 14718699
- Scharf S Mander A Ugoni A Vajda F Christophidis N. A double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer's disease. Neurology 1999; 53: 197– 201. 10408559
- Shrank WH Patrick AR Brookhart MA. Healthy user and related biases in observational studies of preventive interventions: a primer for physicians. J Gen Intern Med 2011; 26: 546– 50. 21203857 PMC3077477
- Soininen H West C Robbins J Niculescu L. Long-term efficacy and safety of celecoxib in Alzheimer's disease. Dement Geriatr Cogn Disord 2007; 23: 8– 21. 17068392
- Szekely CA Breitner JC Fitzpatrick AL Rea TD Psaty BM Kuller LH, et al NSAID use and dementia risk in the Cardiovascular Health Study: role of ApoE and NSAID type. Neurology 2008; 70: 17– 24. 18003940 PMC2877629
- Szekely CA Zandi PP. Non-steroidal anti-inflammatory drugs and Alzheimer's disease: the epidemiological evidence. CNS Neurol Disord Drug Targets 2010; 9: 132– 9. 20205647
- Tilvis RS Kahonen-Vare MH Jolkkonen J Valvanne J Pitkala KH Strandberg TE. Predictors of cognitive decline and mortality of aged people over a 10-year period. J Gerontol A Biol Sci Med Sci 2004; 59: 268– 74. 15031312
- Vemuri P Lesnick TG Przybelski SA Machulda M Knopman DS Mielke MM, et al Association of lifetime intellectual enrichment with cognitive decline in the older population. JAMA Neurol 2014; 71: 1017– 24. 25054282 PMC4266551
- Vijayaraghavan S Darreh-Shori T Rongve A Berge G Sando SB White LR, et al Association of butyrylcholinesterase-K allele and apolipoprotein E varepsilon4 allele with cognitive decline in dementia with Lewy bodies and Alzheimer's disease. JAD 2016; 50: 567– 76. 26757188
- Wattmo C Londos E Minthon L. Risk factors that affect life expectancy in Alzheimer's disease: a 15-year follow-up. Dement Geriatr Cogn Disord 2014; 38: 286– 99. 24992891
- West R Beeri MS Schmeidler J Hannigan CM Angelo G Grossman HT, et al Better memory functioning associated with higher total and low-density lipoprotein cholesterol levels in very elderly subjects without the apolipoprotein e4 allele. Am J Geriatr Psychiatry 2008; 16: 781– 5. 18757771 PMC2614555
- Whitehair DC Sherzai A Emond J Raman R Aisen PS Petersen RC, et al Influence of apolipoprotein E varepsilon4 on rates of cognitive and functional decline in mild cognitive impairment. Alzheimers Dement 2010; 6: 412– 9. 20813342 PMC2943876
- Wyss-Coray T. Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 2006; 12: 1005– 15. 16960575
- Yan Q Zhang JH Liu HT Babu-Khan S Vassar R Biere AL, et al Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer's disease. J Neurosci 2003; 23: 7504– 9. 12930788 PMC6740758
- Young AL Oxtoby NP Daga P Cash DM Fox NC Ourselin S, et al A data-driven model of biomarker changes in sporadic Alzheimer's disease. Brain 2014; 137: 2564– 77. 25012224 PMC4132648
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- Authors
- Rivers-Auty, J., Mather, A. E., Peters, R., Lawrence, C. B., & Brough, D.
- Affiliations
- Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, UK
- University of East Anglia (GB)
- UNSW Sydney (AU)
- Manchester Academic Health Science Centre (GB)
- Venue
- Brain Communications
- Publisher
- Oxford University Press (OUP)
- Published
- 2020
- Volume
- 2
- Issue
- 2
- Pages
- fcaa109-fcaa109
- ISSN
- 2632-1297 (ISSN-L)
- PMC
- PMC7585697
- OpenAlex
- W3044461528
- Cited by
- 130
- References
- 9
- Citations by year
- 2026: 16 · 2025: 31 · 2024: 29 · 2023: 24 · 2022: 18 · 2021: 12
- FWCI
- 9.85
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Brain Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UTAS Research Repository (acceptedVersion)
- UEA Digital Repository (University of East Anglia) (acceptedVersion)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
- Figshare (submittedVersion, cc-by)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- Alzheimer's Disease Neuroimaging Initiative (U01 AG024904, W81XWH-12-2-0012)
- National Institute on Aging
- National Institute of Biomedical Imaging and Bioengineering
- AbbVie, Alzheimer’s Association
- Alzheimer’s Drug Discovery Foundation
- Araclon Biotech
- BioClinica, Inc.
- Biogen
- Bristol-Myers Squibb Company
- CereSpir, Inc.
- Cogstate
- Eisai, Inc.
- Elan Pharmaceuticals, Inc.
- Eli Lilly and Company
- EuroImmun
- F. Hoffmann-La Roche Ltd
- Genentech, Inc.
- Fujirebio
- GE Healthcare; IXICO Ltd
- Janssen Alzheimer Immunotherapy Research & Development, LLC.
- Johnson & Johnson Pharmaceutical Research & Development LLC.
- Lumosity
- Lundbeck
- Meso Scale Diagnostics, LLC.
- NeuroRx Research
- Neurotrack Technologies
- Novartis Pharmaceuticals Corporation
- Pfizer, Inc.
- Piramal Imaging; Servier
- Takeda Pharmaceutical Company and Transition Therapeutics
- The Canadian Institutes of Health Research (BB/R012504/1, BBS/E/F/000PR10348, BBS/E/F/000PR10351, BB/P01061X/1)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
- Keywords
- Alzheimer's disease, nonsteroidal anti-inflammatory drugs, paracetamol, diclofenac, cognitive decline, confounding, ADNI
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