Nonsteroidal Antiinflammatory Drugs and the Risk of Alzheimer's Disease
Bas A. in 't Veld, M.D., Ph.D., Annemieke Ruitenberg, M.D., Ph.D., Albert Hofman, M.D., Ph.D., Lenore J. Launer, Ph.D., Cornelia M. van Duijn, Ph.D., Theo Stijnen, Ph.D., Monique M.B. Breteler, M.D., Ph.D., and Bruno H.C. Stricker, M.B., Ph.D.
Background Previous studies have suggested that the use of nonsteroidalantiinflammatory drugs (NSAIDs) may help to prevent Alzheimer'sdisease. The results, however, have been inconsistent.
Methods We studied the association between the use of NSAIDsand Alzheimer's disease and vascular dementia in a prospective,population-based cohort study of 6989 subjects 55 years of ageor older who were free of dementia at base line. The risk ofAlzheimer's disease was estimated in relation to the use ofNSAIDs as documented in pharmacy records. We defined four mutuallyexclusive categories of use: nonuse, short-term use (1 monthor less of cumulative use), intermediate-term use (more than1 but less than 24 months of cumulative use), and long-termuse (24 months or more of cumulative use). Adjustments weremade by Cox regression analysis for age, sex, education, smokingstatus, and the use or nonuse of salicylates, histamine H2-receptorantagonists, antihypertensive agents, and hypoglycemic agents.
Results During an average follow-up period of 6.8 years, dementiadeveloped in 394 subjects, of whom 293 had Alzheimer's disease,56 vascular dementia, and 45 other types of dementia. The relativerisk of Alzheimer's disease was 0.95 (95 percent confidenceinterval, 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 thosewith intermediate-term use, and 0.20 (95 percent confidenceinterval, 0.05 to 0.83) in those with long-term use. The riskdid not vary according to age. The use of NSAIDs was not associatedwith a reduction in the risk of vascular dementia.
Conclusions The long-term use of NSAIDs may protect againstAlzheimer's disease but not against vascular dementia.
The neuropathologic features of Alzheimer's disease includethe accumulation of microglia around plaques, a local cytokine-mediatedacute-phase response, and activation of the complement cascade.1,2This inflammatory response may damage neurons and exacerbatethe pathologic processes underlying the disease.3 Nonsteroidalantiinflammatory drugs (NSAIDs) may influence this inflammatoryresponse by inhibiting cyclooxygenase-1 and cyclooxygenase-2and by activating the peroxisome proliferator (PPAR) nucleartranscription factor.4,5,6 In addition, cyclooxygenase-mediatedoxidation is important in the calcium-dependent glutamate-signalingpathway that involves N-methyl-D-aspartate. In this way, NSAIDsmay be able to protect neurons directly by reducing cellularresponses to glutamate.7
The results of observational studies have been inconsistentwith regard to the association between NSAIDs and Alzheimer'sdisease.8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30Some have suggested a protective effect, whereas others havenot. In almost all the studies, information on NSAIDs was obtainedretrospectively from patients or relatives or from medical records.These methods are vulnerable to misclassification of drug exposure.In the Netherlands, computerized pharmacy records are virtuallycomplete sources of information on the delivery of drugs. Weconducted a prospective, population-based cohort study to determinewhether the use of NSAIDs other than aspirin was associatedwith a decreased risk of Alzheimer's disease or vascular dementia.
Methods
Study Population
The Rotterdam Study is a prospective, population-based cohortstudy of neurologic, cardiovascular, locomotor, and ophthalmologicdiseases in elderly persons.31 In brief, all persons 55 yearsof age or older who were living in Ommoord, a suburb of Rotterdam,the Netherlands, were invited to participate in the study between1990 and 1993. Of the 10,275 eligible subjects, 7983 (78 percent)gave written informed consent to participate. They were interviewedat home by trained interviewers on a wide range of topics, includingsocioeconomic background, medical history, and medication use.During subsequent visits to the research center, the subjectsunderwent additional interviews and examinations, includingscreening and clinical workup for dementia. In addition, apolipoproteinE genotyping was performed on coded DNA samples by investigatorswho were unaware of whether the subjects had dementia.32 Nearlyall the participants (99.7 percent) were registered at one ormore of the seven pharmacies serving the Ommoord area. Thesepharmacies are fully automated, and all recorded data on druguse during the period from January 1, 1991, through December31, 1998.
The potential study period consisted of the eight-year periodfrom January 1, 1991, through December 31, 1998. Of the 7983subjects who had agreed to participate, 7528 (94.3 percent)were screened and examined for dementia,33,34 and 7046 werefound to be free of dementia at base line. From this group,we excluded the 57 subjects for whom follow-up ended beforeJuly 1, 1991, because there was less than six months of dataon their history of medication use. Participants were then screenedagain for dementia at a second examination (during 1993 or 1994)and at a third examination (during 1997, 1998, or 1999), asdescribed below. Every member of the final study populationof 6989 subjects was followed until the occurrence of death,a diagnosis of dementia, or the end of the study period, whichwas the date of the last examination unless this examinationwas performed in 1999, in which case the end of the study periodwas defined as December 31, 1998.
Information on the Use of NSAIDs and Other Drugs
Complete information on prescriptions was available in automatedform and included the product name; the international nonproprietaryname of the drug; the number of tablets, capsules, or othervehicle in the filled prescription; the date of delivery ofthe product; the prescribed daily number of tablets to be taken;the drug dosage; and the duration of the prescription period.For comparisons of dosages, we used the "defined daily dose,"which is the average dosage of a drug taken by adults for themain indication, according to the World Health Organization.35All prescriptions for oral NSAIDs filled during follow-up wereused to create time-dependent covariates, as described below.Because oral salicylate-based analgesics, including the platelet-inhibitingsalicylates acetylsalicylic acid (aspirin) and carbaspirin calcium,are pharmacologically related to NSAIDs, separate time-dependentcovariates were also created for these drugs so that we couldstudy their association with Alzheimer's disease.
Ascertainment of Dementia
Both at the base-line examination and at follow-up examinations,the subjects were examined for dementia according to a three-stepprotocol.33,34 First, subjects were screened with the use ofthe Mini–Mental State Examination (on which possible scoresrange from 0 to 30, with lower scores indicating worse cognitivefunction)36 and the Geriatric Mental State Schedule (organiclevel [a subquestionnaire used to screen for an organic syndrome])(where possible scores range from 0 to 5, with higher scoresindicating a higher probability of dementia).37 Second, thosescoring 25 or below on the Mini–Mental State Examinationor scoring 1 or more on the Geriatric Mental State Schedulewere selected for further diagnostic evaluation and were subsequentlyexamined by a physician using the Cambridge Mental Disordersof the Elderly Examination diagnostic interview.38 Third, subjectswho were believed to have dementia were examined by a neurologistand a neuropsychologist and underwent magnetic resonance imagingof the brain.
In addition to undergoing screening for dementia, the subjectswere continuously monitored for cases of dementia during follow-up.33A clinical diagnosis of dementia was made according to the criteriaof the Diagnostic and Statistical Manual of Mental Disorders,third edition, revised, by a panel that reviewed all existinginformation. A subdiagnosis of Alzheimer's disease was madeaccording to the criteria of the National Institute of Neurologicaland Communicative Diseases and Stroke–Alzheimer's Diseaseand Related Disorders Association.39 A subdiagnosis of vasculardementia was made according to the criteria of the NationalInstitute of Neurological Disorders and Stroke–AssociationInternationale pour la Recherche et l'Enseignement en Neurosciences.40The date of onset of dementia was defined as the date midwaybetween the date of the last examination at which the subjectwas deemed to be free of dementia and the date of the examinationat which he or she was given a diagnosis of dementia.
Statistical Analysis
For every subject in the cohort, we calculated the person-timebetween January 1, 1991, and death, a diagnosis of dementia,or the end of the study period, whichever came first. We calculatedthe relative risks of dementia (and 95 percent confidence intervals)with the use of a Cox proportional-hazards model41; the cumulativeuse of each drug was represented by a time-dependent covariate.In the Cox model, age in days was used as the time axis to ensureoptimal adjustment for age.42 We used SAS software (PHREG procedure,version 6.12, SAS Institute, Cary, N.C.) to estimate the age-specificincidence of Alzheimer's disease and vascular dementia in relationto the use of NSAIDs.
Apart from a time-dependent comparison in which any use wascompared with no use, we created time-dependent categoricalvariables by dividing the cumulative use of NSAIDs during thestudy period into four mutually exclusive categories: nonuse,short-term use (1 month or less of cumulative use), intermediate-termuse (more than 1 but less than 24 months of cumulative use),and long-term use (24 months or more of cumulative use). Thesecutoff points were chosen to ensure an adequate number of subjectsin each group and are similar to those used in a previous, long-termprospective study.26 The four time-dependent categorical variableswith respect to cumulative exposure times were represented inthe models by three dummy variables, with nonuse as the referencecategory. In this model, a cohort member could contribute person-timeto more than one category of cumulative exposure. To adjustfor the loss of information by the categorization of duration,we also modeled the relation between cumulative duration andeffect by using quadratic spline regression.43 In addition,in this analysis, we examined the effect on the relative risksof a lag time26,44,45,46 by excluding either the last year orthe last two years before diagnosis. In this way, we dealt withpotential protopathic bias that might be caused by changes inthe use of NSAIDs during the prodromal phase of dementia. Inaddition, we performed a test for trend for each of the threesplines. In a similar manner, time-dependent categorical variableswere constructed with respect to the cumulative duration ofuse of aspirin and of related oral salicylates.
Potential confounding variables included sex, age (as definedabove), level of education, smoking status, duration of useof hypoglycemic agents (as a proxy for the duration of diabetesmellitus), and treatment with histamine H2-receptor antagonistsand antihypertensive agents, which have been reported to beassociated with dementia in previous studies. We also investigatedwhether there was an association between the use of corticosteroidsor nonnarcotic analgesic agents and dementia. To study a possibledose–effect relation with respect to NSAIDs, we dichotomizeddosage around the median (1 vs. >1 defined daily dose perday). In additional analyses, we examined whether age and thepresence of the apolipoprotein E 4 allele modified the effectof NSAIDs on the risk of Alzheimer's disease. Finally, in asubanalysis, we examined whether prior use of estrogen influencedthis risk among the female subjects.
Results
During a total of 47,498 person-years of follow-up, with a meanfollow-up time of 6.8 years per subject, 394 subjects receiveda diagnosis of dementia. Of these patients, 293 had Alzheimer'sdisease, 56 vascular dementia, and 45 other types of dementia.Characteristics of the study population are given in Table 1.Diclofenac, ibuprofen, and naproxen together accounted for approximately83 percent of the total number of prescriptions for NSAIDs (Table 2).A greater proportion of the subjects with less than sixyears of education than of those with six or more years of educationtook NSAIDs during follow-up (66 percent vs. 60 percent). Theyearly rate of use was remarkably constant over time, with 37to 40 days of use per 1000 person-days during the 8 years offollow-up; the mean duration of a prescription varied between26.3 and 31.4 days. The total number of NSAID prescriptionsduring the follow-up period was 23,685. The average daily numberof medicines used by subjects with dementia was 2.7, as comparedwith 1.9 in those without dementia (P<0.001). In total, 2314subjects (33.1 percent) had used aspirin or related oral salicylates,almost invariably in doses that inhibit platelets but do nothave antiinflammatory activity (<300 mg per day).
Table 2. Use of NSAIDs by the Study Cohort during the Eight-Year Study Period (1991 to 1998).
Use of an NSAID at any time, defined as a binary, time-dependentvariable and compared with no use at any time, was associatedwith a lower risk of Alzheimer's disease (relative risk, 0.86;95 percent confidence interval, 0.66 to 1.09). Relative to therisk in those who did not use NSAIDs, the risk of Alzheimer'sdisease was 0.95 (95 percent confidence interval, 0.70 to 1.29)in those whose cumulative NSAID use was categorized as short-termuse, 0.83 (95 percent confidence interval, 0.62 to 1.11) inthose with intermediate-term use, and 0.20 (95 percent confidenceinterval, 0.05 to 0.83) in those with long-term use. These riskreductions could not be attributed to the use of a particularNSAID. No association was found between the use of NSAIDs andthe risk of vascular dementia (Table 3). In subjects who tookoral salicylates, we found no association between these drugsand the risk of Alzheimer's disease, but this group did havean increased risk of vascular dementia, which increased withthe duration of use (Table 3). As Figure 1 shows, there wasa gradual decline in the relative risk of Alzheimer's diseasewith increasing duration of NSAID use. This trend became moreprominent when lag times of one and two years were taken intoaccount in the analyses.
Figure 1. The Relative Risk of Alzheimer's Disease in Relation to the Cumulative Duration of NSAID Use after Base Line.
The curves were generated with the use of three quadratic spline regressions, one without lag time, one with a lag time of one year (meaning the exclusion from the analysis of the year before diagnosis), and one with a lag time of two years. They reveal a consistently decreasing risk of Alzheimer's disease with increasing cumulative duration of NSAID use (P for trend=0.06 for the analysis with no lag time, P for trend=0.05 for the analysis with a lag time of one year, and P for trend=0.04 for the analysis with a lag time of two years). The course of the curve at cumulative durations of use of less than 400 days can probably be explained by misclassification of drug use, since there were both subjects who were already using NSAIDs on a long-term basis at base line (and for whom the precise cumulative duration of NSAID exposure could not be calculated, because data on drug use before base line were not available) and new users with less than 400 days of cumulative exposure after base line. The apparent increase in risk seen in the curve without lag time may be explained in part by an increased use of NSAIDs in the prodromal phase of Alzheimer's disease. The increase in risk disappears when a lag time is included.
To investigate whether subjects who had normal cognitive functionat base line (1991) but in whom Alzheimer's disease developedfive or more years later (in 1995 through 1998) were alreadytaking fewer NSAIDs than other subjects in 1991, we stratifiedthe new cases of Alzheimer's disease into those diagnosed duringthe period from 1991 through 1994 and those diagnosed duringthe period from 1995 through 1998. For the period from 1991through 1994, the crude relative risk of Alzheimer's diseasein aspirin users was 1.17 (95 percent confidence interval, 0.85to 1.62), and for the period from 1995 through 1998, the cruderelative risk was 0.72 (95 percent confidence interval, 0.51to 1.02). Of those with long-term cumulative use of NSAIDs,86 percent were already taking these drugs at base line. Ofthose with intermediate-term use, 51 percent were taking NSAIDsat base line, and of those with short-term use, 20 percent weredoing so at base line.
Among the subjects with two or more years of cumulative useof NSAIDs, there was no significant difference in the reductionin the risk of Alzheimer's disease between those taking lessthan one or one defined daily dose per day (relative risk ascompared with no use, 0.17; 95 percent confidence interval,0.02 to 1.22) and those taking more than one defined daily doseper day (relative risk, 0.25; 95 percent confidence interval,0.03 to 1.78). There was no significant difference in the reductionin the risk of Alzheimer's disease with any use between personsless than 80 years of age (relative risk as compared with nouse, 0.23; 95 percent confidence interval, 0.03 to 1.71) andpersons 80 years of age or older (relative risk, 0.18; 95 percentconfidence interval, 0.03 to 1.31). We used this cutoff pointbecause there were only 11 subjects who already had Alzheimer'sdisease before 75 years of age. This fact relates to the highmean age at base line of this cohort and the selection of subjectswho were free of cognitive dysfunction at the start of the study.Because there were no subjects with at least one apolipoproteinE 4 allele among those with long-term cumulative use of NSAIDs,the relative risk among such users could not be estimated. However,among the subjects with less than 24 months but more than 1month of cumulative exposure to NSAIDs, there was no significantdifference in the reduction in the risk between those with atleast one apolipoprotein E 4 allele (relative risk as comparedwith no use, 0.73; 95 percent confidence interval, 0.45 to 1.19)and those with two apolipoprotein E 3 alleles (relative risk,0.94; 95 percent confidence interval, 0.63 to 1.40). No associationwas found between the risk of Alzheimer's disease and the useof nonnarcotic analgesics or corticosteroids. Furthermore, adjustmentfor the use of estrogen did not substantially alter the estimatesof risk in women.
Discussion
In this prospective, population-based study, we found a significantlyreduced risk of Alzheimer's disease in subjects who had takenNSAIDs for a cumulative period of 24 months or more. This reductionwas not modified by age or apolipoprotein E genotype. The useof NSAIDs was not associated with a reduction in the risk ofvascular dementia. Our results are compatible with the hypothesisthat inflammatory mechanisms may play a part in Alzheimer'sdisease. The results are also in line with those of some longitudinalstudies26,28 but not all.22,24,25,29,30 In the Baltimore LongitudinalStudy of Aging,26 the risk of Alzheimer's disease was significantlylower among subjects who took NSAIDs for two or more years thanamong nonusers. Although the results of the latter study arein accordance with our findings, assessment of drug exposurewas based on extrapolated, cross-sectional data acquired duringinterviews at biennial examinations. Drug-exposure data gatheredthis way are probably more vulnerable to misclassification thandata from pharmacy records, especially with respect to the durationof use and the doses taken.
In the current study, a cohort of subjects who were screenedand found to be free of dementia at base line was followed forup to eight years. Since follow-up information was almost complete,selection bias was eliminated. The main concern regarding mostprevious studies of the association between NSAIDs and the riskof Alzheimer's disease has been the potential for misclassificationof the use of drugs. For example, persons with preclinical dementiamight more easily forget and not report their medication historythan persons with normal cognitive function. To overcome thispotential source of information bias, we drew data on the useof NSAIDs from pharmacy records. The information in these pharmacyrecords was independent of characteristics such as age, sex,and cognitive status, and thus we avoided the limitations ofsimilar studies in which information on the use of NSAIDs wasobtained from interviews or medical records. Until 1995, NSAIDscould be obtained in the Netherlands only by prescription, andmost over-the-counter analgesics consist of acetaminophen, whichhas no appreciable antiinflammatory properties. Moreover, inour study, nonnarcotic analgesics other than NSAIDs did notprotect against Alzheimer's disease. Since 1995, some NSAIDshave become available in low doses on an over-the-counter basis.Even if the use of over-the-counter medications led to misclassificationof NSAID exposure in our study cohort, however, this sourceof bias would underestimate, rather than overestimate, a truerisk reduction.
A limitation of our study is that we had no data on the useof NSAIDs before 1991. However, since 86 percent of subjectswith 24 months or more of cumulative use were already takingNSAIDs in 1991, it is likely that they took these drugs on along-term basis. Confounding by indication may explain the increasedrisk of vascular dementia among subjects who took platelet-inhibitingsalicylates, because patients who take these drugs for thisindication may have a higher base-line risk of vascular dementia.However, it does not explain the reduced risk of Alzheimer'sdisease among those who took NSAIDs, since there was no associationbetween the presence of rheumatoid arthritis or osteoarthritisat base line and the risk of Alzheimer's disease. Another potentialsource of confounding that we investigated is related to thepossibility that persons with preclinical dementia may experienceless pain or may communicate their pain less clearly than unaffectedpersons. If they take fewer NSAIDs, a spurious protective effectwould be found. This assumes, however, that before dementiaoccurs, there is no difference in the use of NSAIDs and thatin those in whom dementia develops, the use of NSAIDs will insidiouslydecrease. In our study, however, the use of NSAIDs was alreadylower five years before the diagnosis of dementia, when cognitivefunction was still normal. Another argument against this potentialsource of confounding is the fact that NSAIDs had no protectiveeffect against vascular dementia, whereas one might then expectthat the same direction and magnitude of confounding would haveoccurred. Moreover, less use of medical care would probablyalso mean that, overall, patients with dementia would take fewerdrugs. On the contrary, we found a higher prevalence of overalldrug use in persons with dementia.
In conclusion, our results suggest that long-term use of NSAIDshas a beneficial effect on the risk of Alzheimer's disease.Primary-prevention trials should be undertaken to confirm thisfinding and show whether the benefits of such therapy outweighthe potential risks.
Supported by the Inspectorate for Health Care, the NetherlandsIncentives Program for Geriatric Research, the Netherlands Organizationfor Scientific Research, and the municipality of Rotterdam.
We are indebted to the general practitioners and pharmacistsof Ommoord and of the Rotterdam Regional Institute for AmbulatoryMental Health Care, Noord Rotterdam, for their collaboration.
Source Information
From the Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, the Netherlands (B.A.V., A.R., A.H., C.M.D., T.S., M.M.B.B., B.H.C.S.); the Epidemiology, Demography, and Biometry Program, National Institute on Aging, National Institutes of Health, Bethesda, Md. (L.J.L.); and the Inspectorate for Health Care, The Hague, the Netherlands (B.A.V., B.H.C.S.).
Address reprint requests to Dr. Stricker at the Department of Epidemiology and Biostatistics, Erasmus Medical Center, P.O. Box 1738, 3000 DR Rotterdam, the Netherlands.
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(PPAR
1 vs. >1 defined daily dose per day). In additional analyses, we examined whether age and the presence of the apolipoprotein E 
4 allele modified the effect of NSAIDs on the risk of Alzheimer's disease. Finally, in a subanalysis, we examined whether prior use of estrogen influenced this risk among the female subjects. 
