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Current Alzheimer Research

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ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

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Review Article

Non-steroidal Anti-inflammatory Drugs as Candidates for the Prevention or Treatment of Alzheimer’s Disease: Do they Still Have a Role?

Author(s): Alberto Villarejo-Galende*, Marta González-Sánchez, Víctor A. Blanco-Palmero, Sara Llamas-Velasco and Julián Benito-León

Volume 17, Issue 11, 2020

Page: [1013 - 1022] Pages: 10

DOI: 10.2174/1567205017666201127163018

Price: $65

Abstract

Purpose of Review: To provide an updated analysis of the possible use of non-steroidal anti-inflammatory drugs (NSAIDs) as treatments for Alzheimer´s disease (AD).

Recent Findings: Neuroinflammation in AD is an active field of research, with increasing evidence from basic and clinical studies for an involvement of innate or adaptive immune responses in the pathophysiology of AD. Few clinical trials with anti-inflammatory drugs have been performed in the last decade, with negative results.

Summary: Besides the information gathered from basic research, epidemiological studies have provided conflicting findings, with most case-control or prevalence studies suggesting an inverse relationship between NSAIDs use and AD, but divided results in prospective population-based incident cohort studies. Clinical trials with different NSAIDs are almost unanimous in reporting an absence of clear benefit in AD.

Conclusion: The modulation of inflammatory responses is a promising therapeutic strategy in AD. After three decades of research, it seems that conventional NSAIDs are not the best pharmacological option, both for their lack of clear effects and for an unfavorable side-effect profile in long-term treatment. The development of other anti-inflammatory drugs as candidate treatments in AD may benefit from the knowledge acquired with NSAIDs.

Keywords: NSAIDs, amyloid, Alzheimer´s disease, risk, clinical trials, anti-inflammatory drugs.

« Previous Next »
[1]
Weltgesundheitsorganisation Alzheimer’s Disease International,editors. 2012.
[2]
Scheltens P, Blennow K, Breteler MMB, et al. Alzheimer’s disease. Lancet 2016; 388(10043): 505-17.
[http://dx.doi.org/10.1016/S0140-6736(15)01124-1] [PMID: 26921134]
[3]
Heneka MT, Carson MJ, El Khoury J, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol 2015; 14(4): 388-405.
[http://dx.doi.org/10.1016/S1474-4422(15)70016-5] [PMID: 25792098]
[4]
McGeer PL, Itagaki S, Tago H, McGeer EG. Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett 1987; 79(1-2): 195-200.
[http://dx.doi.org/10.1016/0304-3940(87)90696-3] [PMID: 3670729]
[5]
Süß P, Schlachetzki JCM. Microglia in Alzheimer’s Disease. Curr Alzheimer Res 2020; 17(1): 29-43.
[http://dx.doi.org/10.2174/1567205017666200212155234] [PMID: 32048973]
[6]
McGeer PL, Rogers J, McGeer EG. Inflammation, anti-inflammatory agents, and Alzheimer’s disease: the last 22 years. J Alzheimers Dis 2016; 54(3): 853-7.
[7]
Carmona S, Zahs K, Wu E, Dakin K, Bras J, Guerreiro R. The role of TREM2 in Alzheimer’s disease and other neurodegenerative disorders. Lancet Neurol 2018; 17(8): 721-30.
[http://dx.doi.org/10.1016/S1474-4422(18)30232-1] [PMID: 30033062]
[8]
Bradshaw EM, Chibnik LB, Keenan BT, et al. Alzheimer Disease Neuroimaging Initiative. CD33 Alzheimer’s disease locus: altered monocyte function and amyloid biology. Nat Neurosci 2013; 16(7): 848-50.
[http://dx.doi.org/10.1038/nn.3435] [PMID: 23708142]
[9]
Griciuc A, Serrano-Pozo A, Parrado AR, et al. Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 2013; 78(4): 631-43.
[http://dx.doi.org/10.1016/j.neuron.2013.04.014] [PMID: 23623698]
[10]
Laske C, Stransky E, Hoffmann N, et al. Macrophage colony-stimulating factor (M-CSF) in plasma and CSF of patients with mild cognitive impairment and Alzheimer’s disease. Curr Alzheimer Res 2010; 7(5): 409-14.
[http://dx.doi.org/10.2174/156720510791383813] [PMID: 20455868]
[11]
Domingues C, da Cruz E, Silva OAB, Henriques AG. Impact of cytokines and chemokines on Alzheimer’s disease neuropathological hallmarks. Curr Alzheimer Res 2017; 14(8): 870-82.
[http://dx.doi.org/10.2174/1567205014666170317113606] [PMID: 28317487]
[12]
Labzin LI, Heneka MT, Latz E. Innate immunity and neurodegeneration. Annu Rev Med 2018; 69(69): 437-49.
[http://dx.doi.org/10.1146/annurev-med-050715-104343] [PMID: 29106805]
[13]
Gate D, Saligrama N, Leventhal O, et al. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature 2020; 577(7790): 399-404.
[http://dx.doi.org/10.1038/s41586-019-1895-7] [PMID: 31915375]
[14]
Paouri E, Georgopoulos S. Systemic and CNS inflammation crosstalk: implications for Alzheimer’s disease. Curr Alzheimer Res 2019; 16(6): 559-74.
[http://dx.doi.org/10.2174/1567205016666190321154618] [PMID: 30907316]
[15]
McGeer PL, McGeer E, Rogers J, Sibley J. Anti-inflammatory drugs and Alzheimer disease. Lancet 1990; 335(8696): 1037.
[http://dx.doi.org/10.1016/0140-6736(90)91101-F] [PMID: 1970087]
[16]
Patel NS, Paris D, Mathura V, Quadros AN, Crawford FC, Mullan MJ. Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer’s disease. J Neuroinflammation 2005; 2(1): 9.
[http://dx.doi.org/10.1186/1742-2094-2-9] [PMID: 15762998]
[17]
Ramlackhansingh AF, Brooks DJ, Greenwood RJ, et al. Inflammation after trauma: microglial activation and traumatic brain injury. Ann Neurol 2011; 70(3): 374-83.
[http://dx.doi.org/10.1002/ana.22455] [PMID: 21710619]
[18]
Ashraf GM, Tarasov VV, Makhmutova A, et al. The possibility of an infectious etiology of Alzheimer disease. Mol Neurobiol 2019; 56(6): 4479-91.
[http://dx.doi.org/10.1007/s12035-018-1388-y] [PMID: 30338482]
[19]
Lleo A, Galea E, Sastre M. Molecular targets of non-steroidal anti-inflammatory drugs in neurodegenerative diseases. Cell Mol Life Sci 2007; 64(11): 1403-18.
[http://dx.doi.org/10.1007/s00018-007-6516-1] [PMID: 17447008]
[20]
Hoozemans JJ, Rozemuller AJ, Janssen I, De Groot CJ, Veerhuis R, Eikelenboom P. Cyclooxygenase expression in microglia and neurons in Alzheimer’s disease and control brain. Acta Neuropathol 2001; 101(1): 2-8.
[http://dx.doi.org/10.1007/s004010000251] [PMID: 11194936]
[21]
Hoozemans JJM, Rozemuller JM, van Haastert ES, Veerhuis R, Eikelenboom P. Cyclooxygenase-1 and -2 in the different stages of Alzheimer’s disease pathology. Curr Pharm Des 2008; 14(14): 1419-27.
[http://dx.doi.org/10.2174/138161208784480171] [PMID: 18537664]
[22]
Andreasson KI, Savonenko A, Vidensky S, et al. Age-dependent cognitive deficits and neuronal apoptosis in cyclooxygenase-2 transgenic mice. J Neurosci 2001; 21(20): 8198-209.
[http://dx.doi.org/10.1523/JNEUROSCI.21-20-08198.2001] [PMID: 11588192]
[23]
Choi S-H, Bosetti F. Cyclooxygenase-1 null mice show reduced neuroinflammation in response to beta-amyloid. Aging 2009; 1(2): 234-44.
[http://dx.doi.org/10.18632/aging.100021] [PMID: 20157512]
[24]
Choi S-H, Langenbach R, Bosetti F. Genetic deletion or pharmacological inhibition of cyclooxygenase-1 attenuate lipopolysaccharide-induced inflammatory response and brain injury. FASEB J 2008; 22(5): 1491-501.
[http://dx.doi.org/10.1096/fj.07-9411com] [PMID: 18162486]
[25]
Choi S-H, Aid S, Caracciolo L, et al. Cyclooxygenase-1 inhibition reduces amyloid pathology and improves memory deficits in a mouse model of Alzheimer’s disease. J Neurochem 2013; 124(1): 59-68.
[http://dx.doi.org/10.1111/jnc.12059] [PMID: 23083210]
[26]
Weggen S, Eriksen JL, Das P, et al. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 2001; 414(6860): 212-6.
[http://dx.doi.org/10.1038/35102591] [PMID: 11700559]
[27]
Lleó A, Berezovska O, Herl L, et al. Nonsteroidal anti-inflammatory drugs lower Abeta42 and change presenilin 1 conformation. Nat Med 2004; 10(10): 1065-6.
[http://dx.doi.org/10.1038/nm1112] [PMID: 15448688]
[28]
Sastre M, Dewachter I, Landreth GE, et al. Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase. J Neurosci 2003; 23(30): 9796-804.
[http://dx.doi.org/10.1523/JNEUROSCI.23-30-09796.2003] [PMID: 14586007]
[29]
Sastre M, Dewachter I, Rossner S, et al. Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgamma. Proc Natl Acad Sci USA 2006; 103(2): 443-8.
[http://dx.doi.org/10.1073/pnas.0503839103] [PMID: 16407166]
[30]
Camacho IE, Serneels L, Spittaels K, Merchiers P, Dominguez D, De Strooper B. Peroxisome-proliferator-activated receptor gamma induces a clearance mechanism for the amyloid-beta peptide. J Neurosci 2004; 24(48): 10908-17.
[http://dx.doi.org/10.1523/JNEUROSCI.3987-04.2004] [PMID: 15574741]
[31]
Hoozemans JJM, Veerhuis R, Rozemuller JM, Eikelenboom P. Soothing the inflamed brain: effect of non-steroidal anti-inflammatory drugs on Alzheimer’s disease pathology. CNS Neurol Disord Drug Targets 2011; 10(1): 57-67.
[http://dx.doi.org/10.2174/187152711794488665] [PMID: 21143138]
[32]
The Canadian Study of Health and Aging. risk factors for Alzheimer’s disease in Canada. Neurology 1994; 44(11): 2073-80.
[http://dx.doi.org/10.1212/WNL.44.11.2073] [PMID: 7969962]
[33]
Lucca U, Tettamanti M, Forloni G, Spagnoli A. Nonsteroidal antiinflammatory drug use in Alzheimer’s disease. Biol Psychiatry 1994; 36(12): 854-6.
[http://dx.doi.org/10.1016/0006-3223(94)90598-3] [PMID: 7893851]
[34]
Andersen K, Launer LJ, Ott A, Hoes AW, Breteler MM, Hofman A. Do nonsteroidal anti-inflammatory drugs decrease the risk for Alzheimer’s disease? The Rotterdam Study. Neurology 1995; 45(8): 1441-5.
[http://dx.doi.org/10.1212/WNL.45.8.1441] [PMID: 7644037]
[35]
Anthony JC, Breitner JC, Zandi PP, et al. Reduced prevalence of AD in users of NSAIDs and H2 receptor antagonists: the Cache County study. Neurology 2000; 54(11): 2066-71.
[http://dx.doi.org/10.1212/WNL.54.11.2066] [PMID: 10851364]
[36]
Broe GA, Grayson DA, Creasey HM, et al. Anti-inflammatory drugs protect against Alzheimer disease at low doses. Arch Neurol 2000; 57(11): 1586-91.
[http://dx.doi.org/10.1001/archneur.57.11.1586] [PMID: 11074790]
[37]
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(2): 179-85.
[http://dx.doi.org/10.1097/00019442-200303000-00008] [PMID: 12611747]
[38]
Breitner JC, Gau BA, Welsh KA, et al. Inverse association of anti-inflammatory treatments and Alzheimer’s disease: initial results of a co-twin control study. Neurology 1994; 44(2): 227-32.
[http://dx.doi.org/10.1212/WNL.44.2.227] [PMID: 8309563]
[39]
Beard CM, Waring SC, O’Brien PC, Kurland LT, Kokmen E. Nonsteroidal anti-inflammatory drug use and Alzheimer’s disease: a case-control study in Rochester, Minnesota, 1980 through 1984. Mayo Clin Proc 1998; 73(10): 951-5.
[http://dx.doi.org/10.4065/73.10.951] [PMID: 9787743]
[40]
Vlad SC, Miller DR, Kowall NW, Felson DT. Protective effects of NSAIDs on the development of Alzheimer disease. Neurology 2008; 70(19): 1672-7.
[http://dx.doi.org/10.1212/01.wnl.0000311269.57716.63] [PMID: 18458226]
[41]
Chang K-H, Hsu Y-C, Hsu C-C, et al. Prolong exposure of NSAID in patients With RA will decrease the risk of dementia: a nationwide population-based cohort study. Medicine 2016; 95(10)e3056
[http://dx.doi.org/10.1097/MD.0000000000003056] [PMID: 26962833]
[42]
Yip AG, Green RC, Huyck M, Cupples LA, Farrer LA. MIRAGE Study Group. Nonsteroidal anti-inflammatory drug use and Alzheimer’s disease risk: the MIRAGE Study. BMC Geriatr 2005; 5: 2.
[http://dx.doi.org/10.1186/1471-2318-5-2] [PMID: 15647106]
[43]
in ’t Veld BA, Launer LJ, Hoes AW, et al. NSAIDs and incident Alzheimer’s disease. The Rotterdam Study. Neurobiol Aging 1998; 19(6): 607-11.
[http://dx.doi.org/10.1016/S0197-4580(98)00096-7] [PMID: 10192221]
[44]
Stewart WF, Kawas C, Corrada M, Metter EJ. Risk of Alzheimer’s disease and duration of NSAID use. Neurology 1997; 48(3): 626-32.
[http://dx.doi.org/10.1212/WNL.48.3.626] [PMID: 9065537]
[45]
in t’ Veld BA, Ruitenberg A, Hofman A, et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N Engl J Med 2001; 345(21): 1515-21..
[46]
Zandi PP, Anthony JC, Hayden KM, Mehta K, Mayer L, Breitner JCS. Cache County Study Investigators. Reduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County Study. Neurology 2002; 59(6): 880-6.
[http://dx.doi.org/10.1212/WNL.59.6.880] [PMID: 12297571]
[47]
Lindsay J, Laurin D, Verreault R, et al. Risk factors for Alzheimer’s disease: a prospective analysis from the Canadian Study of Health and Aging. Am J Epidemiol 2002; 156(5): 445-53.
[http://dx.doi.org/10.1093/aje/kwf074] [PMID: 12196314]
[48]
Szekely CA, Breitner JCS, Fitzpatrick AL, et al. NSAID use and dementia risk in the Cardiovascular Health Study: role of APOE and NSAID type. Neurology 2008; 70(1): 17-24.
[http://dx.doi.org/10.1212/01.wnl.0000284596.95156.48] [PMID: 18003940]
[49]
Côté S, Carmichael P-H, 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(3): 219-26.
[http://dx.doi.org/10.1016/j.jalz.2011.03.012] [PMID: 22546354]
[50]
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(3): 135-43.
[http://dx.doi.org/10.1159/000075957] [PMID: 15084783]
[51]
Ancelin M-L, Carrière I, Helmer C, et al. Steroid and nonsteroidal anti-inflammatory drugs, cognitive decline, and dementia. Neurobiol Aging 2012; 33(9): 2082-90.
[http://dx.doi.org/10.1016/j.neurobiolaging.2011.09.038] [PMID: 22071123]
[52]
Wichmann MA, Cruickshanks KJ, Carlsson CM, et al. NSAID use and incident cognitive impairment in a population-based cohort. Alzheimer Dis Assoc Disord 2016; 30(2): 105-12.
[http://dx.doi.org/10.1097/WAD.0000000000000098] [PMID: 26079710]
[53]
Breitner JCS, Haneuse SJPA, Walker R, et al. Risk of dementia and AD with prior exposure to NSAIDs in an elderly community-based cohort. Neurology 2009; 72(22): 1899-905.
[http://dx.doi.org/10.1212/WNL.0b013e3181a18691] [PMID: 19386997]
[54]
Szekely CA, Green RC, Breitner JCS, et al. No advantage of A beta 42-lowering NSAIDs for prevention of Alzheimer dementia in six pooled cohort studies. Neurology 2008; 70(24): 2291-8.
[http://dx.doi.org/10.1212/01.wnl.0000313933.17796.f6] [PMID: 18509093]
[55]
Saag KG, Rubenstein LM, Chrischilles EA, Wallace RB. Nonsteroidal antiinflammatory drugs and cognitive decline in the elderly. J Rheumatol 1995; 22(11): 2142-7.
[PMID: 8596158]
[56]
Fourrier A, Letenneur L, Bégaud B, Dartigues JF. Nonsteroidal antiinflammatory drug use and cognitive function in the elderly: inconclusive results from a population-based cohort study. J Clin Epidemiol 1996; 49(10): 1201.
[http://dx.doi.org/10.1016/0895-4356(96)00202-8] [PMID: 8827002]
[57]
Hanlon JT, Schmader KE, Landerman LR, et al. Relation of prescription nonsteroidal antiinflammatory drug use to cognitive function among community-dwelling elderly. Ann Epidemiol 1997; 7(2): 87-94.
[http://dx.doi.org/10.1016/S1047-2797(96)00124-X] [PMID: 9099396]
[58]
Henderson AS, Jorm AF, Christensen H, Jacomb PA, Korten AE. Aspirin, anti-inflammatory drugs and risk of dementia. Int J Geriatr Psychiatry 1997; 12(9): 926-30.
[http://dx.doi.org/10.1002/(SICI)1099-1166(199709)12:9<926:AID-GPS665>3.0.CO;2-Y] [PMID: 9309471]
[59]
Jonker C, Comijs HC, Smit JH. Does aspirin or other NSAIDs reduce the risk of cognitive decline in elderly persons? Results from a population-based study. Neurobiol Aging 2003; 24(4): 583-8.
[http://dx.doi.org/10.1016/S0197-4580(02)00188-4] [PMID: 12714115]
[60]
Kang JH, Grodstein F. Regular use of nonsteroidal anti-inflammatory drugs and cognitive function in aging women. Neurology 2003; 60(10): 1591-7.
[http://dx.doi.org/10.1212/01.WNL.0000065980.33594.B7] [PMID: 12771247]
[61]
Hayden KM, Zandi PP, Khachaturian AS, et al. Cache County Investigators. Does NSAID use modify cognitive trajectories in the elderly? The Cache County study. Neurology 2007; 69(3): 275-82.
[http://dx.doi.org/10.1212/01.wnl.0000265223.25679.2a] [PMID: 17636065]
[62]
Arvanitakis Z, Grodstein F, Bienias JL, et al. Relation of NSAIDs to incident AD, change in cognitive function, and AD pathology. Neurology 2008; 70(23): 2219-25.
[http://dx.doi.org/10.1212/01.wnl.0000313813.48505.86] [PMID: 18519870]
[63]
Rozzini R, Ferrucci L, Losonczy K, Havlik RJ, Guralnik JM. Protective effect of chronic NSAID use on cognitive decline in older persons. J Am Geriatr Soc 1996; 44(9): 1025-9.
[http://dx.doi.org/10.1111/j.1532-5415.1996.tb02932.x] [PMID: 8790225]
[64]
Wang W, Sun Y, Zhang D. Association between non-steroidal anti-inflammatory drug use and cognitive decline: a systematic review and meta-analysis of prospective cohort Studies. Drugs Aging 2016; 33(7): 501-9.
[http://dx.doi.org/10.1007/s40266-016-0379-9] [PMID: 27235094]
[65]
Benito-León J, Contador I, Vega S, Villarejo-Galende A, Bermejo-Pareja F. .Non-steroidal anti-inflammatory drugs use in older adults decreases risk of Alzheimer’s disease mortality. PLoS One 2019; 14(9): e0222505..
[http://dx.doi.org/10.1371/journal.pone.0222505]
[66]
McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease: a review of 17 epidemiologic studies. Neurology 1996; 47(2): 425-32.
[http://dx.doi.org/10.1212/WNL.47.2.425] [PMID: 8757015]
[67]
Etminan M, Gill S, Samii A. Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer’s disease: systematic review and meta-analysis of observational studies. BMJ 2003; 327(7407): 128.
[http://dx.doi.org/10.1136/bmj.327.7407.128] [PMID: 12869452]
[68]
Szekely CA, Thorne JE, Zandi PP, et al. Nonsteroidal anti-inflammatory drugs for the prevention of Alzheimer’s disease: a systematic review. Neuroepidemiology 2004; 23(4): 159-69.
[http://dx.doi.org/10.1159/000078501] [PMID: 15279021]
[69]
de Craen AJM, Gussekloo J, Vrijsen B, Westendorp RGJ. Meta-analysis of nonsteroidal antiinflammatory drug use and risk of dementia. Am J Epidemiol 2005; 161(2): 114-20.
[http://dx.doi.org/10.1093/aje/kwi029] [PMID: 15632261]
[70]
Wang J, Tan L, Wang H-F, et al. Anti-inflammatory drugs and risk of Alzheimer’s disease: an updated systematic review and meta-analysis. J Alzheimers Dis 2015; 44(2): 385-96.
[http://dx.doi.org/10.3233/JAD-141506] [PMID: 25227314]
[71]
Zhang C, Wang Y, Wang D, Zhang J, Zhang F. NSAID exposure and risk of Alzheimer’s disease: an updated meta-analysis from cohort studies. Front Aging Neurosci 2018; 10: 83.
[http://dx.doi.org/10.3389/fnagi.2018.00083] [PMID: 29643804]
[72]
Mackenzie IR, Munoz DG. Nonsteroidal anti-inflammatory drug use and Alzheimer-type pathology in aging. Neurology 1998; 50(4): 986-90.
[http://dx.doi.org/10.1212/WNL.50.4.986] [PMID: 9566383]
[73]
Halliday GM, Shepherd CE, McCann H, et al. Effect of anti-inflammatory medications on neuropathological findings in Alzheimer disease. Arch Neurol 2000; 57(6): 831-6.
[http://dx.doi.org/10.1001/archneur.57.6.831] [PMID: 10867780]
[74]
Sonnen JA, Larson EB, Walker RL, et al. Nonsteroidal anti-inflammatory drugs are associated with increased neuritic plaques. Neurology 2010; 75(13): 1203-10.
[http://dx.doi.org/10.1212/WNL.0b013e3181f52db1] [PMID: 20811000]
[75]
Rogers J, Kirby LC, Hempelman SR, et al. Clinical trial of indomethacin in Alzheimer’s disease. Neurology 1993; 43(8): 1609-11.
[http://dx.doi.org/10.1212/WNL.43.8.1609] [PMID: 8351023]
[76]
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(1)e1475
[http://dx.doi.org/10.1371/journal.pone.0001475] [PMID: 18213383]
[77]
Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA. Tarenflurbil Phase II Study investigators. Efficacy and safety of tarenflurbil in mild to moderate Alzheimer’s disease: a randomised phase II trial. Lancet Neurol 2008; 7(6): 483-93.
[http://dx.doi.org/10.1016/S1474-4422(08)70090-5] [PMID: 18450517]
[78]
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(1): 197-201.
[http://dx.doi.org/10.1212/WNL.53.1.197] [PMID: 10408559]
[79]
Aisen PS, Schmeidler J, Pasinetti GM. Randomized pilot study of nimesulide treatment in Alzheimer’s disease. Neurology 2002; 58(7): 1050-4.
[http://dx.doi.org/10.1212/WNL.58.7.1050] [PMID: 11940691]
[80]
Aisen PS, Schafer KA, Grundman M, et al. Alzheimer’s Disease Cooperative Study. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA 2003; 289(21): 2819-26.
[http://dx.doi.org/10.1001/jama.289.21.2819] [PMID: 12783912]
[81]
Reines SA, Block GA, Morris JC, et al. Rofecoxib Protocol 091 Study Group. Rofecoxib: no effect on Alzheimer’s disease in a 1-year, randomized, blinded, controlled study. Neurology 2004; 62(1): 66-71.
[http://dx.doi.org/10.1212/WNL.62.1.66] [PMID: 14718699]
[82]
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(1): 8-21.
[http://dx.doi.org/10.1159/000096588] [PMID: 17068392]
[83]
Lyketsos CG, Breitner JC, Green RC, et al. ADAPT Research Group. Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial. Neurology 2007; 68(21): 1800-8.
[http://dx.doi.org/10.1212/01.wnl.0000260269.93245.d2] [PMID: 17460158]
[84]
Breitner JC, Baker LD, Montine TJ, et al. ADAPT Research Group. Extended results of the Alzheimer’s disease anti-inflammatory prevention trial. Alzheimers Dement 2011; 7(4): 402-11.
[http://dx.doi.org/10.1016/j.jalz.2010.12.014] [PMID: 21784351]
[85]
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(6): 714-23.
[http://dx.doi.org/10.1016/j.jalz.2012.11.012] [PMID: 23562431]
[86]
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(2): 216-25.e1.
[http://dx.doi.org/10.1016/j.jalz.2014.03.009] [PMID: 25022541]
[87]
Meyer P-F, Tremblay-Mercier J, Leoutsakos J, et al. INTREPAD: a randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease Neurology 2019; 92(18): 2070-80..
[http://dx.doi.org/10.1212/WNL.0000000000007232]
[88]
Aisen PS, Davis KL, Berg JD, et al. A randomized controlled trial of prednisone in Alzheimer’s disease. Alzheimer’s Disease Cooperative Study. Neurology 2000; 54(3): 588-93.
[http://dx.doi.org/10.1212/WNL.54.3.588] [PMID: 10680787]
[89]
Van Gool WA, Weinstein HC, Scheltens P, Walstra GJ, Scheltens PK. Effect of hydroxychloroquine on progression of dementia in early Alzheimer’s disease: an 18-month randomised, double-blind, placebo-controlled study. Lancet 2001; 358(9280): 455-60.
[http://dx.doi.org/10.1016/S0140-6736(01)05623-9] [PMID: 11513909]
[90]
Butchart J, Brook L, Hopkins V, et al. Etanercept in Alzheimer disease: a randomized, placebo-controlled, double-blind, phase 2 trial. Neurology 2015; 84(21): 2161-8.
[http://dx.doi.org/10.1212/WNL.0000000000001617] [PMID: 25934853]
[91]
Thal LJ, Ferris SH, Kirby L, et al. Rofecoxib Protocol 078 study group. A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment. Neuropsychopharmacology 2005; 30(6): 1204-15.
[http://dx.doi.org/10.1038/sj.npp.1300690] [PMID: 15742005]
[92]
Cardiovascular and cerebrovascular events in the randomized, controlled Alzheimer’s Disease Anti-Inflammatory Prevention Trial (ADAPT). PLoS Clin Trials 2006; 1(7)e33
[http://dx.doi.org/10.1371/journal.pctr.0010033] [PMID: 17111043]
[93]
Bentham P, Gray R, Sellwood E, Hills R, Crome P, Raftery J. AD2000 Collaborative Group. Aspirin in Alzheimer’s disease (AD2000): a randomised open-label trial. Lancet Neurol 2008; 7(1): 41-9.
[http://dx.doi.org/10.1016/S1474-4422(07)70293-4] [PMID: 18068522]
[94]
Green RC, Schneider LS, Amato DA, et al. Tarenflurbil Phase 3 Study Group. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA 2009; 302(23): 2557-64.
[http://dx.doi.org/10.1001/jama.2009.1866] [PMID: 20009055]
[95]
Pasqualetti P, Bonomini C, Dal Forno G, et al. A randomized controlled study on effects of ibuprofen on cognitive progression of Alzheimer’s disease. Aging Clin Exp Res 2009; 21(2): 102-10.
[http://dx.doi.org/10.1007/BF03325217] [PMID: 19448381]
[96]
Hershey LA, Lipton RB. Naproxen for presymptomatic Alzheimer disease: Is this the end, or shall we try again? Neurology 2019; 92(18): 829-30.
[http://dx.doi.org/10.1212/WNL.0000000000007233] [PMID: 30952790]
[97]
Policicchio S, Ahmad AN, Powell JF, Proitsi P. Rheumatoid arthritis and risk for Alzheimer’s disease: a systematic review and meta-analysis and a Mendelian Randomization study . Sci Rep 2017; 7(1): 12861..
[http://dx.doi.org/10.1038/s41598-017-13168-8]
[98]
Wallin K, Solomon A, Kåreholt I, Tuomilehto J, Soininen H, Kivipelto M. Midlife rheumatoid arthritis increases the risk of cognitive impairment two decades later: a population-based study. J Alzheimers Dis 2012; 31(3): 669-76.
[http://dx.doi.org/10.3233/JAD-2012-111736] [PMID: 22647255]
[99]
Zhou M, Xu R, Kaelber DC, Gurney ME. Tumor Necrosis Factor (TNF) blocking agents are associated with lower risk for Alzheimer’s disease in patients with rheumatoid arthritis and psoriasis. PLoS One 2020; 15(3)e0229819
[http://dx.doi.org/10.1371/journal.pone.0229819] [PMID: 32203525]
[100]
Solomon DH, Karlson EW, Rimm EB, et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation 2003; 107(9): 1303-7.
[http://dx.doi.org/10.1161/01.CIR.0000054612.26458.B2] [PMID: 12628952]
[101]
Lai KSP, Liu CS, Rau A, et al. Peripheral inflammatory markers in Alzheimer’s disease: a systematic review and meta-analysis of 175 studies. J Neurol Neurosurg Psychiatry 2017; 88(10): 876-82.
[http://dx.doi.org/10.1136/jnnp-2017-316201] [PMID: 28794151]
[102]
Stefaniak J, O’Brien J. Imaging of neuroinflammation in dementia: a review. J Neurol Neurosurg Psychiatry 2016; 87(1): 21-8.
[PMID: 26384512]
[103]
Galimberti D, Scarpini E. Pioglitazone for the treatment of Alzheimer’s disease. Expert Opin Investig Drugs 2017; 26(1): 97-101.
[http://dx.doi.org/10.1080/13543784.2017.1265504] [PMID: 27885860]
[104]
Seok H, Lee M, Shin E, Yun MR, Lee Y-H, Moon JH, et al. Low-dose pioglitazone can ameliorate learning and memory impairment in a mouse model of dementia by increasing LRP1 expression in the hippocampus . Sci Rep 2019; 9(1): 4414..
[http://dx.doi.org/10.1038/s41598-019-40736-x]
[105]
Heneka MT, Kummer MP, Stutz A, et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 2013; 493(7434): 674-8.
[http://dx.doi.org/10.1038/nature11729] [PMID: 23254930]
[106]
Ising C, Venegas C, Zhang S, et al. NLRP3 inflammasome activation drives tau pathology. Nature 2019; 575(7784): 669-73.
[http://dx.doi.org/10.1038/s41586-019-1769-z] [PMID: 31748742]
[107]
Koronyo Y, Salumbides BC, Sheyn J, et al. Therapeutic effects of glatiramer acetate and grafted CD115+ monocytes in a mouse model of Alzheimer’s disease. Brain 2015; 138(Pt 8): 2399-422.
[http://dx.doi.org/10.1093/brain/awv150] [PMID: 26049087]

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