Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer's disease: systematic review and meta-analysis of observational studies
BMJ 2003; 327 doi: https://doi.org/10.1136/bmj.327.7407.128 (Published 17 July 2003) Cite this as: BMJ 2003;327:128
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The systematic review and meta-analysis by Etminan et al. (2003)1 is
well presented, but sadly it adds little to current knowledge about NSAIDs
in Alzheimer’s disease (AD). Hence, I am somewhat surprised at the undue
prominence it was afforded by the BMJ through front cover emphasis. The
majority of epidemiological surveys published over the past couple of
decades has clearly shown that people maintained on NSAIDs (presumably for
rheumatoid arthritis, osteoarthritis and other inflammatory conditions)
are less likely to develop AD compared to those who are not receiving
NSAIDs. However, association should not and cannot imply causation. A
major confounding factor limiting the value of many of these observational
studies, and by implication this systematic review, is the presence of
various inflammatory processes and conditions predating AD. This is very
difficult to adjust for since NSAIDs were specifically prescribed to treat
such conditions and not AD. It remains unclear whether mechanisms liked to
the presence of concurrent inflammatory conditions such as rheumatoid
arthritis, and not NSAIDs treatment, are responsible for the reduced risk
observed for the development of AD.
Laboratory and animal studies have implicated inflammatory processes
in the pathogenesis of Alzheimer’s disease. This is further supported by
reports that some NSAIDs may decrease beta-amyloid generation.2 Therefore,
it is reasonable to assess whether NSAIDs provide some protection against
the development of AD. However, an appropriate approach for such an
assessment allowing a meaningful conclusion is through randomized double-
blind placebo-controlled trials in individuals who are not suffering from
osteoarthritis and various inflammatory disorders. This is now needed in
order to establish with a degree of certainty whether long term use of
NSAIDs may protect individuals from developing AD, and indeed, such trials
are currently underway.3
Another important question which needs to be addressed is whether
NSAIDs may help those individuals who already have early AD. To date, no
evidence exists to support the use of indomethacin and ibuprofen in such
patients.4 Likewise, the largest multi-centre randomized controlled trial
yet on this subject has found that naproxen and rofecoxib did not slow
cognitive decline in mild to moderate AD.5 All NSAIDS may potentially
cause serious side effects, especially, in an elderly population.
Therefore, clear evidence must exist before NSAIDs can be recommended for
AD either as prophylactic or therapeutic agents. To date, no such clinical
evidence exists. It is unlikely that epidemiological observations, which
are extremely useful in many instances, will contribute any further to
this specific question.
References:
1 Etminan M, Gill S, Samii A. Effects of non-steroidal anti-
inflammatory drugs on risk of Alzheimer’s disease: systematic review and
meta-analysis of observational studies. BMJ 2003;327:128-31 (July 19th).
2 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.
3 Launer LJ. Nonsteroidal anti-inflammatory drugs and Alzheimer’s
disease: What next? JAMA 2003;289:2865-7.
4 Tabet N, Feldman H. Ibuprofen for Alzheimer’s disease. Cochrane
Database Systematic Reviews 3003;2:CD004031.
5 Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M, Davis KL, et
al. Effects of Rofecoxib or Naproxen vs placebo on Alzheimer disease
progression: a randomised controlled trial. JAMA 2003;289;2819-26.
Competing interests:
None declared
Competing interests: No competing interests
To the Editor:
In the July 19 issue of BMJ, Etminan, Gill, and Samii present a
concise and well done systematic review and meta-analysis on nonsteroidal
anti-inflammatory drug (NSAID) use and the risk of developing subsequent
Alzheimer’s Disease (AD)(1) . The trials included in the review were
observational studies (6 cohort and 3 case-control). While theoretic
mechanisms for protection against AD exist (prevention of senile plaque
formation), the authors point out that currently, no randomized
controlled trials (RCT) have examined the role of NSAIDs in prevention of
AD.
As the Women’s Health Initiative (2) has shown us, it is risky to
overstate the findings of observational studies. In light of the lack of
RCT evidence, the authors’ conclusions that “NSAIDs offer some protection
against the development of Alzheimer’s disease” (in the abstract) and “Our
results…show that use of an NSAID lowers the risk of developing
Alzheimer’s disease” (in the discussion section) are overstated. The
authors later correctly note that the appropriate dose, duration, and
risk/benefit of NSAID use for AD protection are unclear (as well as the
appropriate population for a prevention strategy). Pending RCTs to
address these issues, it is best to note that NSAID use is associated with
a decreased risk of AD.
David Price, MD, FAAFP
Director of Education, Colorado Permanente Medical Group, Denver,
Colorado, USA
Associate Professor of Family Medicine and Psychiatry, University of
Colorado Health Sciences Center, Denver, Colorado, USA
references:
1. 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;327:128-132.
2. Writing Group for the Women’s Health Initiative Investigators.
Risks and benefits of estrogen plus progestin in healthy postmenopausal
women: Principal results from the Women’s Health Initiative randomized
controlled trial. JAMA 2002;288:321-333.
Competing interests:
None declared
Competing interests: No competing interests
The recent meta-analysis by Etminan et al.1 concludes that non-
steroidal anti-inflammatory drugs (NSAIDs) are associated with a reduced
risk of developing Alzheimer's disease (AD), with degree of protection
increasing with duration of use. This result is likely correct since
inflammation has been identified as a risk factor for AD.2-4 Additional
studies since October 2002 have also found evidence supporting NSAIDs as
risk reduction factors for AD.5 Other studies are underway.6
One paper suggests combining NSAIDs with other substances.7 While NSAIDs
are very likely able to reduce the risk of AD, as pointed out by the
author of the first paper linking NSAIDs to reduced risk of AD, "these
drugs strike at the periphery of the inflammatory reaction. Much better
results might be obtained if drugs were found that could inhibit the
activation of microglia or the complement system in brain, and
combinations of drugs aimed at different inflammatory targets might be
much more effective than single agents."8 Also, NSAIDs have the
associated risks including gastrointestinal bleeding, which affects up to
5% of those using them.9
On the other hand, recent studies have found that NSAIDs do not
retard the progression of AD.10,11 However, treatment of AD once it gets
past the initial stages is another matter.12,13
An alternate approach for reducing inflammation in the brain is
through n-3 fatty acids such as those found in fish oil (eicosapentaenoic
acid (EPA) and docosahexaenoic acid (DHA)) and, perhaps, flaxseed oil.14
Indeed, fish consumption was identified as a risk reduction factor for AD
in a pioneering ecologic study15 and confirmed in a pair of subsequent
cohort studies.16,17 Fish oil has also been found to reduce the
inflammation associated with rheumatoid arthritis,18,19 and has been found
beneficial for a large number of diseases and conditions. 20 Fish oil has
two additional advantages over NSAIDs: 1 - it provides fatty acids that
are very important for proper brain function; 21 and 2 - it has few
adverse side effects, although consumption of fish is also associated with
ingestion of mercury and other toxic and hazardous chemicals, and global
fish stocks are being depleted by over fishing.22
The better way to go about reducing the risk of AD is through proper
diet. As shown in Grant, total energy and total fat are important risk
factors for AD, while fish and cereals are risk reduction factors. Based
on a suggestion by the author,23 the findings for energy, fat, and cereals
were confirmed,24 but only for those with the APOE epsilon 4 allele. The
finding regarding fat has been refined to relate to saturated fat and
trans-fatty acids.25,26
Alzheimer's disease is a horrible disease and a variety of approaches
to reduce the risk will be more effective than any one way. The health
community is encouraged to continue research on the mechanisms that lead
to AD and ways to reduce the risk.
References
1. 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;327:128.
2. Townsend KP, Obregon D, Quadros A, Patel N, Volmar Ch, Paris D,
Mullan M. Proinflammatory and vasoactive effects of Abeta in the
cerebrovasculature. Ann N Y Acad Sci. 2002;977:65-76.
3. Gupta A, Pansari K. Inflammation and Alzheimer's disease. Int J
Clin Pract. 2003;57:36-9.
4. Quinn J, Montine T, Morrow J, Woodward WR, Kulhanek D, Eckenstein
F. Inflammation and cerebral amyloidosis are disconnected in an animal
model of Alzheimer's disease. J Neuroimmunol. 2003;137:32-41.
5. 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.
6. Tabet N, Feldmand H. Ibuprofen for Alzheimer's disease. Cochrane
Database Syst Rev. 2003;(2):CD004031.
7. Prasad KN, Cole WC, Prasad KC. Risk factors for Alzheimer's
disease: role of multiple antioxidants, non-steroidal anti-inflammatory
and cholinergic agents alone or in combination in prevention and
treatment. J Am Coll Nutr. 2002;21:506-22.
8. McGeer PL, McGeer EG. Local neuroinflammation and the progression
of Alzheimer's disease. J Neurovirol. 2002;8:529-38.
9. Laine L. The gastrointestinal effects of nonselective NSAIDs and
COX-2-selective inhibitors. Semin Arthritis Rheum. 2002;32:25-32.
10. Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M, Davis KL,
Farlow MR, Jin S, Thomas RG, Thal LJ; Alzheimer's Disease Cooperative
Study. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease
progression: a randomized controlled trial. JAMA. 2003;289:2819-26.
11. Launer L. Nonsteroidal anti-inflammatory drug use and the risk
for Alzheimer's disease: dissecting the epidemiological evidence. Drugs.
2003;63:731-9.
12. Corey-Bloom J. The ABC of Alzheimer's disease: cognitive changes
and their management in Alzheimer's disease and related dementias. Int
Psychogeriatr. 2002;14(Suppl 1):51-75.
13. Grossberg GT. The ABC of Alzheimer's disease: behavioral symptoms
and their treatment. Int Psychogeriatr. 2002;14(Suppl 1):27-49.
14. Morris DH. Methodologic challenges in designing clinical studies
to measure differences in the bioequivalence of n-3 fatty acids. Mol Cell
Biochem. 2003;246:83-90.
15. Grant WB. Dietary links to Alzheimer's disease. Alz Dis Rev.
1997;2:42-55
http://www.mc.uky.edu/adreview/Vol2/Grant/grant.pdf
17. Morris CM, Evans DA, Bienias JL, et al. Consumption of fish and n
-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol.
2003;60:940-6.
16. Barberger-Gateau P, Letenneur L, Deschamps V, Pérès K, Jean-
François Dartigues JF, Renaud S. Fish, meat, and risk of dementia: cohort
study. BMJ 2002;325:932-3.
18. James MJ, Gibson RA, Cleland LG. Dietary polyunsaturated fatty
acids and inflammatory mediator production. Am J Clin Nutr. 2000;71:343S-
8S.
19. Kremer JM. n-3 fatty acid supplements in rheumatoid arthritis.
Am J Clin Nutr. 2000;71:349S-51S.
20. Simopoulos AP. Essential fatty acids in health and chronic
disease. Am J Clin Nutr. 1999;70:560S-9S.
21. Haag M. Essential fatty acids and the brain. Can J Psychiatry.
2003;48:195-203.
22. Myers RA, Worm B. Rapid worldwide depletion of predatory fish
communities. Nature 2003;423:280-3.
23. Grant WB. The APOE-epsilon4 allele and Alzheimer disease among
African Americans, Hispanics, and Whites. JAMA. 1998;280:162-163.
24. Luchsinger JA, Tang MX, Shea S, Mayeux R. Caloric intake and the
risk of Alzheimer disease. Arch Neurol. 2002;59:1258-63.
25. Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Aggarwal
N, Schneider J, Wilson RS. Dietary fats and the risk of incident Alzheimer
disease. Arch Neurol. 2003;60:194-200.
26. Cooper JL. Dietary lipids in the aetiology of Alzheimer's
disease; Implications for thearapy. Drugs Aging 2003;20:399-418.
Competing interests:
None declared
Competing interests: No competing interests
I congratulate Etminan and colleagues on their meta-analysis.
The suggestion that aspirin might reduce the risk of Alzheimer’s
disease has important public health implications. Another recent
observational study of over 700 elderly individuals provides further
evidence to support this suggestion (1) but demonstrating a reduction via
a randomised controlled trial will be more difficult. One reason is that
many of the elderly individuals who could be entered into such a trial
would already be eligible to receive aspirin for cardiovascular
prophylaxis.
How then do we formulate policy to move forward? Perhaps we are
approaching a time when all individuals over the age of 50 years without
contraindications should be advised to take low-dose aspirin to reduce
their risk of age related conditions such as cardiovascular disease,
cancer and Alzheimer’s disease (2). Such policy must complement other
disease reduction approaches and would require careful implementation to
ensure that health inequalities are reduced rather than increased.
Reference
1. Nilsson SE, Johansson B, Takkinen S, Berg S, Zarit S, McClearn G,
Melander A. Does aspirin protect against Alzheimer’s disease? A study in
a Swedish population-based sample aged =/>80 years. Eur J Clin
Pharmacol 2003 Jun 25 [Epub ahead of print]
2. Morgan G. A qualitative illustration of the public health potential of
aspirin. Medical Hypotheses 2003;60(6):900-902.
Competing interests:
None declared
Competing interests: No competing interests
I was disapointed not to see any acknowledgment of possible
confounding factors for what is currently only an observed reduction in
risk. What if having osteoarthritis is negatively associated with
developing Alzheimer's? Presumably some form of OA is the likely reason
why older people are on NSAIDs. Both conditions have genetic and
environmental components which may well be mutually exclusive.
The statement that 'NSAIDs offer some protection against the
development of Alzheimer's disease' cannot yet be made with confidence. As
Davey Smith and Ebrahim (1)pointed out in a recent BMJ editorial an
association does not show causation and doctors have been caught out
giving poorly based and premature advice (and treatment) before.
A recently published randomised controlled trial failed to show any
benefit from either naproxen or rofecoxib in preventing the progression of
early Alzheimer's disease (2).
Sadly we may be no further forward in being able to prevent or treat
this condition.
Dr Michael Robertson
General Practitioner
Abingdon,
Oxon
(1) Davey Smith, G and Ebrahim, S (2002) Data dredging, bias, or
confounding. BMJ 2002; 325 : 1437-8
(2) Aisen, P. S., Schafer, K. A., Grundman, M., Pfeiffer, E., Sano,
M., Davis, K. L., Farlow, M. R., Jin, S., Thomas, R. G., Thal, L. J.
(2003). Effects of Rofecoxib or Naproxen vs Placebo on Alzheimer Disease
Progression: A Randomized Controlled Trial. JAMA 289: 2819-2826
Competing interests:
None declared
Competing interests: No competing interests
NSAIDs and Alzheimer's: Quality before quantity
Etminan et al. (1) are to be commended for presenting an explicit
report of their systematic review of observational studies investigating
the effects of NSAIDs on Alzheimer's disease. However, the review could
have been strengthened by appraisal of the quality of the included
studies. Poor or highly variable quality of the included studies may
influence the conclusions of a systematic review. In contrast to
systematic reviews of randomised controlled trials (RCTs) no widely
accepted quality assessment tools exist for reviews involving
observational studies (2). We recently developed separate checklists for
considering biases relating to cohort, case-control and cross-sectional
studies in a systematic review of male circumcision for preventing
heterosexual acquisition of HIV in men (3).
We question pooling the results of the studies in this review. Unlike
RCTs, observational studies cannot control for unknown or unmeasured
confounders. The authors' statement that "the possibility of confounding
and bias may be more significant in meta-analysis of observational studies
than meta-analyses of randomised trials", trivializes the difference
between the two situations. Adequately randomised trials can minimise the
likelihood of selection bias and therefore confounding, in contrast to
cohort and case-control studies where this limitation can never be fully
overcome. Even the pooling of adjusted results from individual studies, as
performed in this review, does not eliminate the problem. There is
therefore a real danger that meta-analysis of the included studies may
simply have produced a more precise estimate of already biased findings
(4).
Rather than conclude "the use of an NSAID lowers the risk of
developing Alzheimer's disease", the authors might have drawn attention to
the current lack of reliable evidence and called for RCTs to establish
whether the use of NSAIDs for preventing Alzheimer's disease is warranted
or not. Meta-analysis cannot by itself remove selection bias from
observational data.
1. Mahyar Etminan, Sudeep Gill, and Ali Samii. Effect of non-
steroidal anti-inflammatory drugs on risk of Alzheimer's disease:
systematic review and meta-analysis of observational studies. BMJ, Jul
2003; 128 - 0.
2. J Dinnes, A Sowden, F Song, M Petticrew, J Deeks, D Altman, R D'Amico.
A review of quality assessment tools for non-randomised intervention
studies. Abstract. 3rd Symposium on Systematic Reviews: Beyond the
Basics. Oxford, July 2000.
http://www.ihs.ox.ac.uk/csm/Oralabstract2K.htm#Dinnes (accessed 14 August
2003).
3. Siegfried N, Muller M, Volmink J, Deeks J, Egger M, Low N, Weiss H,
Walker S, Williamson P. Male circumcision for prevention of heterosexual
acquisition of HIV in men (Cochrane Review). In: The Cochrane Library,
Issue 3, 2003. Oxford: Update Software.
4. Egger M, Davey Smith G, Schneider M. Systematic reviews of
observational studies. In Egger M, Davey Smith G, Altman DG (eds).
Systematic reviews in health care: meta-analysis in context. 2nd edition.
BMJ Books, London 2001.
Competing interests:
None declared
Competing interests: No competing interests