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From the Kinsmen Laboratory of Neurological Research, Department of Psychiatry (Drs McGeer and E.G. McGeer) and the Departments of Medicine and Statistics (Dr. Schulzer), University of British Columbia, Vancouver, BC, Canada.
Supported by grants from the Alzheimer Society of B.C. and the Jack Brown and Family A.D. Research Fund, as well as donations from individual British Columbians.
Received November 3, 1995. Accepted in final form January 19, 1996.
Address correspondence and reprint requests to Dr. Patrick L. McGeer, Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.
Alzheimer's disease (AD) lesions are characterized by the presence of numerous inflammatory proteins.This has led to the hypothesis that brain inflammation is a cause of neuronal injury in AD and that anti-inflammatory drugs may act as protective agents. Seventeen epidemiologic studies from nine different countries have now been published in which arthritis, a major indication for the use of anti-inflammatory drugs, or anti-inflammatory drugs themselves have been considered as risk factors for AD. Both factors appear to be associated with a reduced prevalence of AD. The small size of most studies has limited their individual statistical significance, but similarities in design have made it possible to evaluate combined results. We have used established methods of statistical meta-analysis to estimate the overall chance of individuals exposed to arthritis or anti-inflammatory drugs developing AD as compared with the general population. Seven case-control studies with arthritis as the risk factor yielded an overall odds ratio of 0.556 (p < 0.0001), while four case-control studies with steroids yielded odds ratios of 0.656 (p = 0.049) and three case-control studies with nonsteroidal anti-inflammatory drugs (NSAIDs) yielded an odds ratio of 0.496 (p = 0.0002). When NSAIDs and steroids were combined into a single category of anti-inflammatory drugs, the odds ratio was 0.556 (p < 0.0001). Population-based studies were less similar in design than case-control studies, complicating the process of applying statistical meta-analytical techniques. Nevertheless, population-based studies with rheumatoid arthritis and NSAID use as risk factors strongly supported the results of case-control studies. These data suggest anti-inflammatory drugs may have a protective effect against AD. Controlled clinical trials will be necessary to test this possibility.
NEUROLOGY 1996;47: 425-432
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P. Grammas and R. Ovase Cerebrovascular Transforming Growth Factor-{beta} Contributes to Inflammation in the Alzheimer's Disease Brain Am. J. Pathol., May 1, 2002; 160(5): 1583 - 1587. [Abstract] [Full Text] [PDF]
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P. S. Aisen, J. Schmeidler, and G. M. Pasinetti Randomized pilot study of nimesulide treatment in Alzheimer's disease Neurology, April 9, 2002; 58(7): 1050 - 1054. [Abstract] [Full Text] [PDF]
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R. B. Clark The role of PPARs in inflammation and immunity J. Leukoc. Biol., March 1, 2002; 71(3): 388 - 400. [Abstract] [Full Text] [PDF]
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M. Koistinaho, M. I. Kettunen, G. Goldsteins, R. Keinanen, A. Salminen, M. Ort, J. Bures, D. Liu, R. A. Kauppinen, L. S. Higgins, et al. beta -Amyloid precursor protein transgenic mice that harbor diffuse Abeta deposits but do not form plaques show increased ischemic vulnerability: Role of inflammation PNAS, January 24, 2002; (2002) 32670899. [Abstract] [Full Text] [PDF]
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R. C. Petersen, R. Doody, A. Kurz, R. C. Mohs, J. C. Morris, P. V. Rabins, K. Ritchie, M. Rossor, L. Thal, and B. Winblad Current Concepts in Mild Cognitive Impairment Arch Neurol, December 1, 2001; 58(12): 1985 - 1992. [Abstract] [Full Text] [PDF]
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H. YAZAWA, Z.-X. YU, TAKEDA, Y. LE, W. GONG, V. J. FERRANS, J. J. OPPENHEIM, C. C. H. LI, and J. M. WANG {beta} Amyloid peptide (A{beta}42) is internalized via the G-protein-coupled receptor FPRL1 and forms fibrillar aggregates in macrophages FASEB J, November 1, 2001; 15(13): 2454 - 2462. [Abstract] [Full Text] [PDF]
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R. S. Doody, J.C. Stevens, C. Beck, R.M. Dubinsky, J.A. Kaye, L. Gwyther, R.C. Mohs, L.J. Thal, P.J. Whitehouse, S.T. DeKosky, et al. Practice parameter: Management of dementia (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology Neurology, May 8, 2001; 56(9): 1154 - 1166. [Abstract] [Full Text] [PDF]
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 E. G. McGeer and P. L. McGeer Innate Immunity in Alzheimer's Disease: A Model for Local Inflammatory Reactions Mol. Interv., April 1, 2001; 1(1): 22 - 29. [Abstract] [Full Text]
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F. Landi, G. Onder, C. Cattel, G. Gambassi, F. Lattanzio, M. Cesari, A. Russo, and R. Bernabei Functional Status and Clinical Correlates in Cognitively Impaired Community-Living Older People J Geriatr Psychiatry Neurol, March 1, 2001; 14(1): 21 - 27. [Abstract] [PDF]
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L. Ho, D. Purohit, V. Haroutunian, J. D. Luterman, F. Willis, J. Naslund, J. D. Buxbaum, R. C. Mohs, P. S. Aisen, and G. M. Pasinetti Neuronal Cyclooxygenase 2 Expression in the Hippocampal Formation as a Function of the Clinical Progression of Alzheimer Disease Arch Neurol, March 1, 2001; 58(3): 487 - 492. [Abstract] [Full Text] [PDF]
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C. K. Combs, J. C. Karlo, S.-C. Kao, and G. E. Landreth {beta}-Amyloid Stimulation of Microglia and Monocytes Results in TNF{alpha}-Dependent Expression of Inducible Nitric Oxide Synthase and Neuronal Apoptosis J. Neurosci., February 15, 2001; 21(4): 1179 - 1188. [Abstract] [Full Text] [PDF]
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K. D. Bornemann, K.-H. Wiederhold, C. Pauli, F. Ermini, M. Stalder, L. Schnell, B. Sommer, M. Jucker, and M. Staufenbiel A{beta}-Induced Inflammatory Processes in Microglia Cells of APP23 Transgenic Mice Am. J. Pathol., January 1, 2001; 158(1): 63 - 73. [Abstract] [Full Text] [PDF]
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G. A. Broe, D. A. Grayson, H. M. Creasey, L. M. Waite, B. J. Casey, H. P. Bennett, W. S. Brooks, and G. M. Halliday Anti-inflammatory Drugs Protect Against Alzheimer Disease at Low Doses Arch Neurol, November 1, 2000; 57(11): 1586 - 1591. [Abstract] [Full Text] [PDF]
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M. T. Heneka, T. Klockgether, and D. L. Feinstein Peroxisome Proliferator-Activated Receptor-gamma Ligands Reduce Neuronal Inducible Nitric Oxide Synthase Expression and Cell Death In Vivo J. Neurosci., September 15, 2000; 20(18): 6862 - 6867. [Abstract] [Full Text] [PDF]
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K. ISHII, F. MUELHAUSER, U. LIEBL, M. PICARD, S. KÜHL, B. PENKE, T. BAYER, M. WIESSLER, M. HENNERICI, K. BEYREUTHER, et al. Subacute NO generation induced by Alzheimer's {beta}-amyloid in the living brain: reversal by inhibition of the inducible NO synthase FASEB J, August 1, 2000; 14(11): 1485 - 1489. [Abstract] [Full Text]
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I. R. A. Mackenzie Activated microglia in dementia with Lewy bodies Neurology, July 12, 2000; 55(1): 132 - 134. [Abstract] [Full Text] [PDF]
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J. C. Anthony, J. C. S. Breitner, P. P. Zandi, M. R. Meyer, I. Jurasova, M. C. Norton, and S. V. Stone Reduced prevalence of AD in users of NSAIDs and H2 receptor antagonists: The Cache County Study Neurology, June 13, 2000; 54(11): 2066 - 2071. [Abstract] [Full Text] [PDF]
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C. E. Shepherd, E. Thiel, H. McCann, A. J. Harding, and G. M. Halliday Cortical Inflammation in Alzheimer Disease but Not Dementia With Lewy Bodies Arch Neurol, June 1, 2000; 57(6): 817 - 822. [Abstract] [Full Text] [PDF]
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G. M. Halliday, C. E. Shepherd, H. McCann, W. G. J. Reid, D. A. Grayson, G. A. Broe, and J. J. Kril Effect of Anti-inflammatory Medications on Neuropathological Findings in Alzheimer Disease Arch Neurol, June 1, 2000; 57(6): 831 - 836. [Abstract] [Full Text] [PDF]
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 C. Petersen, S. Petersen, L. Milas, F. F. Lang, and P. J. Tofilon Enhancement of Intrinsic Tumor Cell Radiosensitivity Induced by a Selective Cyclooxygenase-2 Inhibitor Clin. Cancer Res., June 1, 2000; 6(6): 2513 - 2520. [Abstract] [Full Text]
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 S. Honda, F. Itoh, M. Yoshimoto, S. Ohno, Y. Hinoda, and K. Imai Association Between Complement Regulatory Protein Factor H and AM34 Antigen, Detected in Senile Plaques J. Gerontol. A Biol. Sci. Med. Sci., May 1, 2000; 55(5): 265M - 269. [Abstract] [Full Text]
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 C. Holmes and D. Wilkinson Molecular biology of Alzheimer's disease Advan. Psychiatr. Treat., May 1, 2000; 6(3): 193 - 200. [Full Text]
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 P. E. Lipsky, P. Brooks, L. J. Crofford, R. DuBois, D. Graham, L. S. Simon, L. B. A. van de Putte, and S. B. Abramson Unresolved Issues in the Role of Cyclooxygenase-2 in Normal Physiologic Processes and Disease Arch Intern Med, April 10, 2000; 160(7): 913 - 920. [Abstract] [Full Text] [PDF]
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 A. Castrillo, M. J. M. Díaz-Guerra, S. Hortelano, P. Martín-Sanz, and L. Boscá Inhibition of Ikappa B Kinase and Ikappa B Phosphorylation by 15-Deoxy-Delta 12,14-Prostaglandin J2 in Activated Murine Macrophages Mol. Cell. Biol., March 1, 2000; 20(5): 1692 - 1698. [Abstract] [Full Text]
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P. S. Aisen, K. L. Davis, J. D. Berg, K. Schafer, K. Campbell, R. G. Thomas, M. F. Weiner, M. R. Farlow, M. Sano, M. Grundman, et al. A randomized controlled trial of prednisone in Alzheimer's disease Neurology, February 8, 2000; 54(3): 588 - 588. [Abstract] [Full Text] [PDF]
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I. R. A. Mackenzie Anti-inflammatory drugs and Alzheimer-type pathology in aging Neurology, February 8, 2000; 54(3): 732 - 732. [Abstract] [Full Text] [PDF]
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C. K. Combs, D. E. Johnson, J. C. Karlo, S. B. Cannady, and G. E. Landreth Inflammatory Mechanisms in Alzheimer's Disease: Inhibition of beta -Amyloid-Stimulated Proinflammatory Responses and Neurotoxicity by PPARgamma Agonists J. Neurosci., January 15, 2000; 20(2): 558 - 567. [Abstract] [Full Text] [PDF]
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 D. G. Munoz and H. Feldman Causes of Alzheimer's disease Can. Med. Assoc. J., January 1, 2000; 162(1): 65 - 72. [Abstract] [Full Text] [PDF]
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W. R. Markesbery The Role of Oxidative Stress in Alzheimer Disease Arch Neurol, December 1, 1999; 56(12): 1449 - 1452. [Full Text] [PDF]
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T. J. Montine, K. R. Sidell, B. C. Crews, W. R. Markesbery, L. J. Marnett, L. J. Roberts II, and J. D. Morrow Elevated CSF prostaglandin E2 levels in patients with probable AD Neurology, October 22, 1999; 53(7): 1495 - 1495. [Abstract] [Full Text] [PDF]
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 A. J. Lerner Alzheimer's Disease in Males: Endocrine Issues and Prospects J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3416 - 3419. [Full Text] [PDF]
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T. V. Petrova, K. T. Akama, and L. J. Van Eldik Selective Modulation of BV-2 Microglial Activation by Prostaglandin E2. DIFFERENTIAL EFFECTS ON ENDOTOXIN-STIMULATED CYTOKINE INDUCTION J. Biol. Chem., October 1, 1999; 274(40): 28823 - 28827. [Abstract] [Full Text] [PDF]
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 J. L. Cummings and D. V. Jeste Alzheimer's Disease and Its Management in the Year 2010 Psychiatr Serv, September 1, 1999; 50(9): 1173 - 1177. [Abstract] [Full Text] [PDF]
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K. A. Kelley, L. Ho, D. Winger, J. Freire-Moar, C. B. Borelli, P. S. Aisen, and G. M. Pasinetti Potentiation of Excitotoxicity in Transgenic Mice Overexpressing Neuronal Cyclooxygenase-2 Am. J. Pathol., September 1, 1999; 155(3): 995 - 1004. [Abstract] [Full Text] [PDF]
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