Nonsteroidal Antiinflammatory Drugs and the Risk of Alzheimer's Disease
Open accessAbstract
BACKGROUND: Previous studies have suggested that the use of nonsteroidal antiinflammatory drugs (NSAIDs) may help to prevent Alzheimer's disease. The results, however, are inconsistent. METHODS: We studied the association between the use of NSAIDs and Alzheimer's disease and vascular dementia in a prospective, population-based cohort study of 6989 subjects 55 years of age or older who were free of dementia at base line, in 1991. To detect new cases of dementia, follow-up screening was performed in 1993 and 1994 and again in 1997 through 1999. The risk of Alzheimer's disease was estimated in relation to the use of NSAIDs as documented in pharmacy records. We defined four mutually exclusive categories of use: nonuse, short-term use (1 month or less of cumulative use), intermediate-term use (more than 1 but less than 24 months of cumulative use), and long-term use (24 months or more of cumulative use). Adjustments were made by Cox regression analysis for age, sex, education, smoking status, and the use or nonuse of salicylates, histamine Hz-receptor antagonists, antihypertensive agents, and hypoglycemic agents. RESULTS: During an average follow-up period of 6.8 years, dementia developed in 394 subjects, of whom 293 had Alzheimer's disease, 56 vascular dementia, and 45 other types of dementia. The relative risk of Alzheimer's disease was 0.95 (95 percent confidence interval, 0.70 to 1.29) in subjects with short-term use of NSAIDs, 0.83 (95 percent confidence interval, 0.62 to 1.11) in those with intermediate-term use, and 0.20 (95 percent confidence interval, 0.05 to 0.83) in those with long-term use. The risk did not vary according to age. The use of NSAIDs was not associated with a reduction in the risk of vascular dementia. CONCLUSIONS: The long-term use of NSAIDs may protect against Alzheimer's disease but not against vascular dementia.
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Long-term treatment with NSAIDs reduced the risk for AD, delayed disease onset, and slowed cognitive decline.
“The recognition that a robust inflammatory response contributes to AD also fuelled the discovery that long-term treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) reduced the risk for AD, delayed disease onset, and slowed cognitive decline (McGeer et al., 1996;Stewart et al., 1997;in t' in t'Veld et al., 2001).”
From PPARγ/RXRα-Induced and CD36-Mediated Microglial Amyloid-β Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice (2012) · cites this paper as in t'Veld et al., 2001
The Discussion (page not supplied) reports a significantly lower risk of Alzheimer's disease among people who used NSAIDs for 24 months or more, supporting the risk portion of the claim. This observational study does not establish that NSAIDs caused the reduction, and the passages do not report delayed disease onset or slowed cognitive decline. (LLM, conf=0.88)
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Luchsinger, J. A., & Mayeux, R. P. (2004) · The Lancet Neurology · doi:10.1016/s1474-4422(04)00878-6 · Cited by 434 · see citing works
The impact of systemic infection on the progression of neurodegenerative disease
Perry, V. H., Newman, T. A., & Cunningham, C. (2003) · Nature Reviews Neuroscience · doi:10.1038/nrn1032 · Cited by 428 · see citing works
Neuroinflammatory processes in Alzheimer’s disease
Heneka, M. T., O’Banion, M. K., Terwel, D., & Kummer, M. P. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-010-0438-z · Cited by 433 · see citing works
Visualising microglial activation in vivo
Banati, R. B. (2002) · Glia · doi:10.1002/glia.10144 · Cited by 428 · see citing works
“Some epidemiological studies have found a protective effect of antiinflammatory medication against the risk of developing late-onset Alzheimer-type dementia (McGeer and McGeer, 1995; in t’ Veld et al., 2001) that lends support to this view.”
BackgroundToll-Like Receptors in Neurodegeneration
Okun, E., Griffioen, K., Lathia, J., Tang, S.-C., Mattson, M., & Arumugam, T. (2008) · Brain Research Reviews · doi:10.1016/j.brainresrev.2008.09.001 · Cited by 459 · see citing works
“Neuroinflammation is proposed to play a major role in AD pathogenesis, as long term treatment with non-steroidal antiinflammatory drugs reduces AD risk and may delay disease progression (Stewart et al., 1997; in t' Veld et al., 2001).”
BackgroundInflammatory process in Alzheimer's Disease
Meraz-Ríos, M. A., Toral-Rios, D., Franco-Bocanegra, D., Villeda-Hernández, J., & Campos-Peña, V. (2013) · Frontiers in Integrative Neuroscience · doi:10.3389/fnint.2013.00059 · Cited by 427 · see citing works
“The Rotterdam study (In’T Veld et al., 2001), Multi-Institutional Research Alzheimer’s Genetic Epidemiology Study (Yip et al., 2005) and Canadian Study of Health and Aging (CSHA) (Coté et al., 2012) also observed an association between the NSAID use and a reduced AD risk.”
BackgroundContribution of inflammatory processes to Alzheimer's disease: molecular mechanisms
Sastre, M., Klockgether, T., & Heneka, M. T. (2006) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2005.11.014 · Cited by 426 · see citing works
“Epidemiological studies have documented a beneficial effect of non-steroideal anti-inflammatory drugs (NSAIDs) in AD (Rogers et al., 1993; McGeer et al., 1996; Stewart et al., 1997; Akiyama et al., 2000; In’t Veld et al., 2001; Szekely et al., 2004).”
BackgroundInfluentialThe contribution of neuroinflammation to amyloid toxicity in Alzheimer's disease
Minter, M. R., Taylor, J. M., & Crack, P. J. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13411 · Cited by 451 · see citing works
“Epidemiological evidence suggests that treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), prior to disease onset, can delay AD (in t’ Veld et al. 2001).”
BackgroundClinical manifestations of cerebral amyloid angiopathy–related inflammation
Eng, J. A., Frosch, M. P., Choi, K., Rebeck, G. W., & Greenberg, S. M. (2004) · Annals of Neurology · doi:10.1002/ana.10810 · Cited by 417 · see citing works
NSAIDs and Alzheimer disease: Epidemiological, animal model and clinical studies
McGeer, P. L., & McGeer, E. G. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.03.013 · Cited by 498 · see citing works
Neuroinflammation in Alzheimer's disease and prion disease
Eikelenboom, P., Bate, C., van Gool, W. A., Hoozemans, J. J. M., Rozemüller, A. J. M., Veerhuis, R., & Williams, A. (2002) · Glia · doi:10.1002/glia.10146 · Cited by 402 · see citing works
“The idea that the neuroinflammatory response is an interesting therapeutic target for treatment with antiinflammatory drugs was also strongly supported by epidemiological studies showing that the use of classical NSAIDS can prevent or retard AD (McGeer et al., 1996; in t’ Veld et al., 2001).”
BackgroundA Randomized, Double-Blind, Study of Rofecoxib in Patients with Mild Cognitive Impairment
on behalf of the Rofecoxib Protocol 078 study group, Thal, L. J., Ferris, S. H., Kirby, L., Block, G. A., Lines, C. R., Yuen, E., Assaid, C., Nessly, M. L., Norman, B. A., et al. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300690 · Cited by 402 · see citing works
McGeer, P. L., Schwab, C., Parent, A., & Doudet, D. (2003) · Annals of Neurology · doi:10.1002/ana.10728 · Cited by 400 · see citing works
Nonsteroidal Anti-Inflammatory Drugs for the Prevention of Alzheimer’s Disease: A Systematic Review
Szekely, C. A., Thorne, J. E., Zandi, P. P., Ek, M., Messias, E., Breitner, J. C. S., & Goodman, S. N. (2004) · Neuroepidemiology · doi:10.1159/000078501 · Cited by 394 · see citing works
Apolipoprotein E in Alzheimer's Disease: An Update
Yu, J.-T., Tan, L., & Hardy, J. (2014) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-071013-014300 · Cited by 394 · see citing works
“Additionally, several epidemiological and prospective studies suggest that long-term use of NSAIDs was associated with a significantly lower risk of AD in APOE ε4 subjects (in ‘t Veld et al. 2001, Szekely et al. 2008).”
BackgroundReines, S. A., Block, G. A., Morris, J. C., Liu, G., Nessly, M. L., Lines, C. R., Norman, B., & Baranak, C. C. (2004) · Neurology · doi:10.1212/wnl.62.1.66 · Cited by 378 · see citing works
Nonsteroidal Anti-inflammatory Drugs in Ophthalmology
Kim, S. J., Flach, A. J., & Jampol, L. M. (2010) · Survey of Ophthalmology · doi:10.1016/j.survophthal.2009.07.005 · Cited by 386 · see citing works
Alzheimer Disease: Mechanistic Understanding Predicts Novel Therapies
Selkoe, D. J. (2004) · Annals of Internal Medicine · doi:10.7326/0003-4819-140-8-200404200-00047 · Cited by 381 · see citing works
Yan, Q., Zhang, J., Liu, H., Babu-Khan, S., Vassar, R., Biere, A. L., Citron, M., & Landreth, G. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-20-07504.2003 · Cited by 469 · see citing works
“The observation that chronic NSAID treatment could diminish AD risk (Stewart et al., 1997; in t’ Veld et al., 2001) and alter A plaque pathology in transgenic mice (Lim et al., 2000) led us to examine in greater detail the regulation of A metabolism and deposition by this class of drugs.”
BackgroundThe Rotterdam Study: 2016 objectives and design update
Albert Hofman, D., Brusselle, G., Murad, S. D., van Duijn, C. M., Franco, O. H., Goedegebure, A., Ikram, M. A., Klaver, C. C. W., Nijsten, T. E. C., Peeters, R. P., et al. (2015) · European Journal of Epidemiology · doi:10.1007/s10654-015-0082-x · Cited by 382 · see citing works
Self-citationBlasko, I., Stampfer‐Kountchev, M., Robatscher, P., Veerhuis, R., Eikelenboom, P., & Grubeck‐Loebenstein, B. (2004) · Aging Cell · doi:10.1111/j.1474-9728.2004.00101.x · Cited by 374 · see citing works
Sastre, M., Dewachter, I., Rossner, S., Bogdanovic, N., Rosen, E., Borghgraef, P., Evert, B. O., Dumitrescu-Ozimek, L., Thal, D. R., Landreth, G., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0503839103 · Cited by 373 · see citing works
Hampel, H. J., Mesulam, M. M., Cuello, A. C., Khachaturian, A. S., Vergallo, A., Farlow, M. R., Snyder, P. J., Giacobini, E., & Khachaturian, Z. S. (2019) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2018.43 · Cited by 369 · see citing works
“For example, pharmacoepidemiology data suggest that long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) may protect against AD (74, 75); and at preclinical stages, NSAIDs may diminish significantly AD prevalence (42), while they are ineffective after its clinical presentation (43).”
Gorelick, P. B. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2010.05726.x · Cited by 361 · see citing works
Risk Factors for Vascular Dementia and Alzheimer Disease
Gorelick, P. B. (2004) · Stroke · doi:10.1161/01.str.0000143318.70292.47 · Cited by 365 · see citing works
Montgomery, S. L., & Bowers, W. J. (2011) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-011-9287-2 · Cited by 365 · see citing works
A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease
Hampel, H., Caraci, F., Cuello, A. C., Caruso, G., Nisticò, R., Corbo, M., Baldacci, F., Toschi, N., Garaci, F., Chiesa, P. A., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00456 · Cited by 360 · see citing works
Sastre, M., Dewachter, I., Landreth, G. E., Willson, T. M., Klockgether, T., LEUVEN, F. V., & Heneka, M. T. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-30-09796.2003 · Cited by 359 · 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
Inflammation, defective insulin signaling, and neuronal dysfunction in Alzheimer's disease
Ferreira, S. T., Clarke, J. R., Bomfim, T. R., & Felice, F. G. D. (2014) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2013.12.010 · Cited by 354 · see citing works
Vegeto, E., Benedusi, V., & Maggi, A. C. (2008) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2008.04.001 · Cited by 356 · see citing works
Naturally occurring phytochemicals for the prevention of Alzheimer’s disease
Kim, J., Lee, H. J., & Lee, K. W. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06562.x · Cited by 354 · see citing works
“NSAIDs appear to exert a protective effect against the development of AD (Breitner et al. 1994; in t’ Veld et al. 2001; Zandi et al.”
BackgroundNeuroinflammation: Implications for the Pathogenesis and Molecular Diagnosis of Alzheimer's Disease
Rojo, L. E., Fernández, J. A., Maccioni, A. A., Jimenez, J. M., & Maccioni, R. B. (2008) · Archives of Medical Research · doi:10.1016/j.arcmed.2007.10.001 · Cited by 351 · see citing works
Interleukin-6 Covaries Inversely with Hippocampal Grey Matter Volume in Middle-Aged Adults
Marsland, A. L., Gianaros, P. J., Abramowitch, S. M., Manuck, S. B., & Hariri, A. R. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.04.016 · Cited by 348 · see citing works
Current Pharmacotherapy for Alzheimer's Disease
Lleó, A., Greenberg, S. M., & Growdon, J. H. (2005) · Annual Review of Medicine · doi:10.1146/annurev.med.57.121304.131442 · Cited by 346 · see citing works
Beyond the neuron–cellular interactions early in Alzheimer disease pathogenesis
Henstridge, C. M., Hyman, B. T., & Spires-Jones, T. L. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0113-1 · Cited by 348 · see citing works
Role of inflammation in neurodegenerative diseases
Minghetti, L. (2005) · Current Opinion in Neurology · doi:10.1097/01.wco.0000169752.54191.97 · Cited by 335 · see citing works
Ineffective phagocytosis of amyloid-β by macrophages of Alzheimer's disease patients
Fiala, M., Lin, J., Ringman, J. M., Kermani-Arab, V., Tsao, G., Patel, A. J., Lossinsky, A. S., Graves, M. C., Gustavson, A. R., Sayre, J. W., et al. (2005) · Journal of Alzheimer s Disease · doi:10.3233/jad-2005-7304 · Cited by 328 · see citing works
The Rotterdam Study: 2014 objectives and design update
Albert Hofman, D., Murad, S. D., van Duijn, C. M., Franco, O. H., Goedegebure, A., Ikram, M. A., Klaver, C. C. W., Nijsten, T. E. C., Peeters, R. P., Stricker, B. H. C., et al. (2013) · European Journal of Epidemiology · doi:10.1007/s10654-013-9866-z · Cited by 330 · see citing works
Self-citationExtended results of the Alzheimer's disease anti‐inflammatory prevention trial
Breitner, J. C. S., Baker, L. D., Montine, T. J., Meinert, C. L., Lyketsos, C. G., Ashe, K. H., Brandt, J., Craft, S., Evans, D. A., Green, R. C., et al. (2011) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2010.12.014 · Cited by 327 · see citing works
Systemic infection, interleukin 1beta, and cognitive decline in Alzheimer's disease
Holmes, C. (2003) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.74.6.788 · Cited by 330 · see citing works
Alzheimer's Disease and Mild Cognitive Impairment
Kelley, B. J., & Petersen, R. C. (2007) · Neurologic Clinics · doi:10.1016/j.ncl.2007.03.008 · Cited by 328 · see citing works
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Inflammation and Alzheimer’s disease
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The LPS receptor (CD14) links innate immunity with Alzheimer's disease
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Astrocytes: Implications for Neuroinflammatory Pathogenesis of Alzheimers Disease
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- Authors
- 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.
- Affiliations
- Erasmus MC (NL)
- National Institutes of Health (US)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2001-11-22
- Volume
- 345
- Issue
- 21
- Pages
- 1515-1521
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2083556882
- Semantic Scholar
- 29c01ac52ec50618ec7b3b87ca55b707ca397434
- Cited by
- 1,196
- References
- 44
- Citations by year
- 2026: 13 · 2025: 14 · 2024: 18 · 2023: 23 · 2022: 26 · 2021: 33 · 2020: 23 · 2019: 40 · 2018: 38 · 2017: 28 · 2016: 40 · 2015: 49 · 2014: 49 · 2013: 39 · 2012: 50
- FWCI
- 52.61
- Type
- journal article
- Language
- en
- Open access
- green
- pure.eur.nl
- Licence
- other-oa
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- 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
- nonsteroidal anti-inflammatory drugs, Alzheimer's disease, vascular dementia, dementia risk, long-term NSAID use, older adults
- MeSH terms
- Aged, Alzheimer Disease, Anti-Inflammatory Agents, Non-Steroidal, Drug Administration Schedule, Female, Humans, Male, Middle Aged, Prospective Studies, Risk, Salicylates, Dementia, Vascular, Cohort Studies, Proportional Hazards Models
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