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September 24, 2002; 59 (6) Articles

Reduced incidence of AD with NSAID but not H2 receptor antagonists

The Cache County Study

Peter P. Zandi, James C. Anthony, Kathleen M. Hayden, Kala Mehta, Lawrence Mayer, John C.S. Breitner
First published September 24, 2002, DOI: https://doi.org/10.1212/WNL.59.6.880
Peter P. Zandi
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James C. Anthony
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Kathleen M. Hayden
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Kala Mehta
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Lawrence Mayer
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John C.S. Breitner
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Reduced incidence of AD with NSAID but not H2 receptor antagonists
The Cache County Study
Peter P. Zandi, James C. Anthony, Kathleen M. Hayden, Kala Mehta, Lawrence Mayer, John C.S. Breitner
Neurology Sep 2002, 59 (6) 880-886; DOI: 10.1212/WNL.59.6.880

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Abstract

Background: Previous analyses from the Cache County (UT) Study showed inverse associations between the prevalence of AD and the use of nonsteroidal anti-inflammatory drugs (NSAID), aspirin compounds, or histamine H2 receptor antagonists (H2RA). The authors re-examined these associations using data on incident AD.

Methods: In 1995 to 1996, elderly (aged 65+) county residents were assessed for dementia, with current and former use of NSAID, aspirin, and H2RA as well as three other “control” medication classes also noted. Three years later, interval medication histories were obtained and 104 participants with incident AD were identified among 3,227 living participants. Discrete time survival analyses estimated the risk of incident AD in relation to medication use.

Results: AD incidence was marginally reduced in those reporting NSAID use at any time. Increased duration of use was associated with greater risk reduction, and the estimated hazard ratio was 0.45 with ≥2 years of exposure. Users of NSAID at baseline showed little reduction in AD incidence, regardless of use thereafter. By contrast, former NSAID users showed substantially reduced incidence (estimated hazard ratio = 0.42), with a trend toward greatest risk reduction among those with extended exposure. Similar patterns appeared with aspirin but not with any other medicines examined.

Conclusions: Long-term NSAID use may reduce the risk of AD, provided such use occurs well before the onset of dementia. More recent exposure seems to offer little protection. Recently initiated randomized trials of NSAID for primary prevention of AD are therefore unlikely to show effects with treatment until participants have been followed for several years.

Growing evidence suggests that several commonly used medicines may delay or prevent the onset of AD. Among the most thoroughly studied of these are the nonsteroidal anti-inflammatory drugs (NSAID).1 At least 24 epidemiologic studies have investigated the relationship between NSAID and AD.2-25⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓ A systematic review26 of 16 early studies2-17⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓ provided support for the hypothesis that anti-inflammatory medications, and NSAID in particular, might reduce the risk of AD. More recent studies have reported mixed results, however. There was little support for a beneficial effect of NSAID in two longitudinal studies with relatively short periods of follow-up18,19⇓ and in two nested case–control studies that ascertained exposures from prescription records.20,24⇓ By contrast, two population-based cross-sectional studies21,22⇓ and two long-term prospective studies23,25⇓ found reduced AD risk with NSAID use. The latter prospective studies were noteworthy because of their size and duration of observation. One followed 1,686 elderly subjects over a 15-year period,23 and the other followed 7,046 subjects over 7 years and ascertained exposures directly from pharmacy records.25 Both found a risk reduction for AD with NSAID use, with an effect that increased when duration of use was longer and, most notably, when the analyses interposed a 2-year lag period between exposure and onset of AD.

Definitive demonstration of neuroprotection against AD with NSAID will require carefully designed randomized trials. To date, several trials have tested the efficacy of different anti-inflammatory strategies for the treatment of AD, examining attenuation of the expected progression of symptoms. Although, the results from one early trial appeared promising,27 subsequent trials have failed to show any benefit.28-30⇓⇓ Failure of an agent to modify established AD dementia does not, however, imply failure of the agent to delay or prevent initial onset of clinical features. Thus, the efficacies of both a conventional NSAID (naproxen) and a selective cyclo-oxygenase-2 (COX) inhibitor (celecoxib) are being investigated currently in the Alzheimer’s Disease Anti-Inflammatory Prevention Trial (ADAPT; www.2stopAD.org), a large primary prevention trial. The results from ADAPT will not be available for several years. In the meantime, further investigation with well-designed observational studies may shed additional light on what to expect as this trial proceeds.

We previously reported analyses of prevalence data from the Cache County Study, which suggested reduced occurrence of AD associated with NSAID, aspirin compounds, and histamine-2 receptor antagonists (H2RA).21 Here, we report the results from similar analyses of newly obtained prospective data from the same study population. Our aims were to evaluate whether use of NSAID was associated with reduced AD incidence in the Cache County sample and whether the apparent reduction in risk (if any) depended on duration or recency of NSAID exposure. We also sought to evaluate whether any observed association varied as a function of age or the presence of ε4 alleles at APOE, the polymorphic genetic locus for apoE. Finally, we examined whether our earlier findings with H2RA could be replicated. Results from other previous studies of H2RA have been mixed,8,31⇓ and to our knowledge no prospective study of H2RA and AD has been reported.

Methods.

Study population.

The Cache County Study is an ongoing, population-based investigation of dementing disorders and their genetic and environmental antecedents. Two waves of study have now been completed. In 1995 to 1997, we used a multistage procedure (Wave I)32 to identify and diagnose prevalent cases of dementia among the elderly residents of Cache County, UT. Some 5,092 individuals (90% of county residents aged 65 years or older on 1 January 1995) agreed to participate in this first wave of study. Over 97% of these respondents also provided buccal DNA for determination of genotype at APOE. Screening began with an in-person interview that included an adaptation of the modified Mini-Mental State Examination (3MS)33 or, for those unable to participate, the Informant Questionnaire for Cognitive Disorder in the Elderly (IQCODE)34 administered to a collateral informant. Participants with suspected cognitive impairment were further evaluated by interviewing their collateral informants with the Dementia Questionnaire (DQ).35 DQ interviews were also assigned to a 19% stratified subsample of high-risk participants, regardless of their results on the 3MS or IQCODE. Participants whose screening results suggested cognitive difficulties as well as all members of the 19% subsample were then fully examined by specially trained nurses and psychometric technicians. The examination included a brief physical assessment, a detailed medical and chronologic history of cognitive symptoms, a structured neurologic examination, and a 1-hour battery of neuropsychological tests. A geriatric psychiatrist and neuropsychologist reviewed these data and assigned working diagnoses of dementia (Diagnostic and Statistical Manual for Mental Disorders, 3rd rev. ed. [DSM-IIIR]) or other cognitive syndromes. Most living participants with working diagnoses of dementia were further examined in person by a geriatric psychiatrist and were referred for laboratory studies including neuroimaging. A consensus panel of experts in neurology, geriatric psychiatry, neuropsychology, and cognitive neuroscience then assigned final diagnoses. AD diagnoses were made using standard research criteria,36 and other diagnostic categories also reflected current research practice.32,37⇓ The expert panel also reviewed prior judgments regarding age at dementia onset (defined as the year when participants unambiguously met DSM-IIIR criteria for dementia). Living participants with dementia or other cognitive impairment were re-examined 18 months later.

Through these procedures, we identified 338 participants with dementia prevalent at the time of their initial assessment. Another 33 individuals were found to have developed dementia after their initial visit and were considered as incident cases. Using data collected from the fully examined 19% subsample,38 we estimated an overall sensitivity of 93% for the study’s screening and examination protocol for detection of prevalent dementia.

Approximately 3 years later, in 1998 to 2000, we used a similar multistage procedure (Wave II)37 to identify incident cases of dementia among these Cache County elderly. A total of 3,411 individuals (83% of those without dementia at Wave I and still living) agreed to participate in the second wave of study. The surviving individuals who did not participate tended to be older (p < 0.001) and less educated (p < 0.001), but they were similar to participants with respect to sex and lifetime use of NSAID (see below). Among those who participated, we identified 152 with incident dementia (another 15 individuals were found to have developed dementia prior to the baseline visit of Wave I but had been missed at that time; these individuals were therefore considered as prevalent cases and not included in the current analyses). Adding the 33 participants with onset of dementia detected in the later stages of Wave I gave a total of 185 incident dementia cases. Using data from participants in the 19% subsample who were fully examined at both waves of study, we estimated that our procedures had an overall sensitivity of 89% for the detection of incident dementia. Of those with incident dementia, 104 had diagnoses of definite, probable, or possible AD36 and no other dementing illness. A comparison of such diagnoses with neuropathologic findings in 54 individuals suggested that the accuracy of our (prevalent and incident) AD differential diagnosis is comparable with typical rates reported from university AD clinics (e.g., positive predictive value 90%; B. Plassman et al., manuscript submitted).

Another 3,123 participants completed the Wave II study procedures sufficiently to assess their cognitive status and were found to be free of dementia. Of these, 394 were members of the high-risk 19% subsample and were examined directly, whereas 2,729 others showed no evidence of dementia on screening measures. A remaining 121 individuals who agreed to participate in the Wave II assessments had evidence of cognitive difficulty upon screening, but they refused further examination and were thus not included in the current analyses. These analyses therefore focus on the 104 participants with incident AD and 3,123 participants without evidence of dementia (total n = 3,227).

Exposure assessment.

At the initial Wave I visit, we administered to all participants (or to their collateral informants, if necessary) a standardized interview that covered a battery of candidate risk or protective factors for dementia. Interviewers asked whether participants had used any prescription or over-the-counter (OTC) medicines in the previous 2 weeks. If “yes,” they asked the respondents to show the containers of these medicines and, for each, recorded the name, treatment indication, strength, dosage form, instructions for use (if any), age at first use, and duration of use. Interviewers then proceeded to ask about former use of prescription or OTC medicines not in current use. To facilitate the recall of such medicine use, they asked a series of probe inquiries about four groups of common illnesses (painful or inflammatory joint ailments, acid-peptic disease or gastroesophageal reflux, anxiety or mood disturbances, and chronic respiratory conditions) as well as their typical remedies. As a memory aid, the most common such medicines were shown to participants on large-print “drug cards.” Interviewers recorded each endorsed medicine along with its indication, dosage, and duration. We followed similar procedures at the screening interview for Wave II, restricting questioning to drug use that was current at the time of the interview or had occurred within the Wave I to II interval.

We focused on six different classes of medicines: nonaspirin NSAID (ibuprofen, naproxen, diclofenac, nabumetone, sulindac, oxaprozin, and others); H2RA (cimetidine, ranitidine, famotidine, and nizatidine); aspirin compounds; nonaspirin, non-NSAID pain relievers (acetaminophen, allopurinol, propoxyphene, and other opioids); simple antacid/antiflatulents (calcium carbonate, aluminum hydroxide/magnesium hydroxide, simethicone, and others); and other non-H2RA stomach remedies (omeprazole, cisapride, sucralfate, anticholinergics, and others). The first three classes constituted our target drugs of primary interest. The latter three categories were included as “control” exposures for which we had no a priori reason to anticipate any association with the risk of AD.

Using data from Wave I, we classified exposure for each of these six classes of medicines by reported lifetime use. Participants were considered as “exposed” to a particular drug class if they reported current or former use of a medicine within that class daily (or at least four doses weekly) for a month or longer. In further analyses, we classified NSAID users by their reported years of use prior to the Wave I interview and by current use at baseline (i.e., at Wave I) versus former use. Only exposures that met minimum criteria for frequency and duration of use (daily or at least four doses weekly for a month or longer) were considered. As did two previous prospective studies, we dichotomized duration at ≤2 years versus >2 years.23,25⇓ Former users were those who reported NSAID use in their lifetime but did not show NSAID among their current medicines.

Statistical analyses.

We compared the characteristics of the elderly in these analyses by their reported use of the six different classes of medicines using χ2 tests as aids to interpretation for categorical variables and two-sample t-tests for continuous variables. We then used discrete time survival analysis39 to compare the risks of AD among the users of each class of medicine versus a reference group of nonusers. The analyses considered each year under observation as a discrete time interval. Participants entered the analytic pool at the age of their initial Wave I interview and were then considered year by year until they either developed AD or underwent Wave II procedures that confirmed their dementia-free status, as initially observed at Wave I. The discrete time survival analyses yielded estimated hazard ratios associated with various exposures and accommodated statistical adjustment for multiple covariates.

All multivariable discrete time survival models were built upon a “base” model that had previously yielded a good fit to the incidence data.37 This base model included covariate terms for age, the squared deviation of age from the sample’s median value, sex, years of education, the presence of one or two APOE ε4 alleles, as well as interactions between age and the APOE ε4 terms. We fit the discrete time survival models using SAS V8 software (SAS, Cary, NC) and report parameter estimates with 95% profile likelihood CI.

Results.

Table 1 compares the characteristics of participants categorized by their reported use of the six different classes of medicines. The few participants (only 1 to 2%) who were unable to provide data on medicine use tended to be older and less educated. Users of each medication class were more likely than nonusers to be women, except for aspirin compounds. Users of aspirin compounds and other non-NSAID pain relievers tended to be slightly older than nonusers, but there were no other notable differences between users and nonusers of these medicines in age or level of education.

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Table 1 Demographic characteristics of 3,227 Cache County elderly included in analyses, classified by sustained use of NSAID, H2RA, aspirin compounds, and three “control” classes of medicines

Table 2 shows the crude and covariate-adjusted estimated hazard ratios of developing AD among users versus nonusers of each class of medicine. Any lifetime use of NSAID was associated with a marginally reduced risk of AD. No evidence suggestive of a protective effect was apparent for aspirin compounds, H2RA, or any of the “control” medicines.

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Table 2 Crude and adjusted HR for development of AD (with 95% CI), estimated from discrete time survival models with lifetime use of NSAID, H2RA, aspirin compounds, and three “control” classes of drugs

Table 3 presents the results of additional analyses specifically with nonaspirin NSAID as a target exposure group. We first tested interaction terms of NSAID with age (Model 1) or with the presence of one or more APOE ε4 alleles (Model 2). The age interaction term may suggest that the inverse association of NSAID and AD decreases with age. By contrast, the interaction with APOE genotype was weak.

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Table 3 Hazard ratios for development of AD (with 95% CI), estimated from discrete time survival models with NSAID

We then examined the apparent influence of duration and recency of NSAID use. Longer duration was associated with greater reduction in risk, so that a significant inverse association appeared between AD and use of NSAID for >2 years (Model 3). Separation of current and former NSAID users revealed a reduced risk only for the latter (Model 4). Among both current and former users, there was a suggestion of greater reduction in risk with increasing duration of use (Model 5). While there was suggestive evidence of an effect among current users who reported substantial prior exposure, the nearly null results among current users were not appreciably altered for those with longer periods of exposure extending forward into the Wave I to II interval (data collected at Wave II) but before the estimated year of onset for dementia (data not shown).

A similar pattern of association with duration and recency was observed with aspirin compounds. Individuals who used aspirin compounds for >2 years had an estimated hazard ratio of 0.57 (95% CI 0.31 to 0.99) for development of AD. Former users with >2 years of reported aspirin exposure showed a still lower estimated hazard ratio of 0.24, but with relatively small numbers under analysis, the 95% CI (0.01 to 1.11) was relatively broad and included 1.0.

Discussion.

These analyses replicate and extend earlier findings from prevalence data in Cache County suggesting a protective effect of NSAID, but with an important clarification. Specifically, in this prospective study, we found increasing duration of nonaspirin NSAID use was associated with stronger reduction in AD risk, whereas current use was not associated with reduced risk unless its duration had extended >2 years prior to the Wave I interview.

Our findings are consistent with those from the Baltimore Longitudinal Study on Aging23 and the Rotterdam Study,25 and they appear to reinforce the “lag period” for effect noted in those two studies. Considered together, the three studies suggest that sustained use of NSAID may delay or prevent AD only if they are taken during a critical window in the latent stages of the disease, before damage to the integrity of the brain is sufficient to provoke demonstrable cognitive symptoms.40 This critical window may end several years prior to the onset of dementia.1,41⇓ If correct, this interpretation could help explain some conflicting findings in the literature and might also explain the disappointing negative results from recent treatment trials with anti-inflammatory agents.28-30⇓⇓

We also found that sustained use of aspirin compounds for >2 years may be similarly associated with reduced risk of AD. This observation reinforces the possible neuroprotective effect with aspirin noted in our previous analyses of prevalence data,21 although results from other studies on aspirin as a separate category have been mixed.22,23,25⇓⇓ As we noted previously, more than two-thirds of Cache County respondents who reported regular aspirin use stated that such use was in low dosage (≤325 mg/day) for purposes of cardiovascular prophylaxis. Aspirin, like other NSAID, inhibits COX, which catalyze the synthesis of prostaglandins. Notably, however, aspirin’s inhibition of COX results from its irreversible covalent bonding (hence, steric inhibition) of the enzyme’s active site.42

It is widely conjectured that, to the extent NSAID protect against AD, they do so by attenuating inflammatory responses in the brain.43 We note, however, that low-dose aspirin is not believed to have potent anti-inflammatory effects. Unfortunately, a lack of precise exposure data limited our abilities to investigate dose effects with NSAID. However, new results from the Rotterdam Study25 and a recent report from Australia22 both note that the apparent neuroprotective effect of NSAID is at least as great with low (analgesic) as with higher (anti-inflam-matory) doses. These findings could therefore suggest other possible mechanisms for NSAID including antiplatelet effects,22 reduction of glutamate-related excitotoxicity (thought to involve COX-2 in postsynaptic signal processing),44 or inhibition of free radical production by intraneuronal COX-2.45 In addition to these effects, recent studies have shown that NSAID may reduce amyloid β-protein load and plaque deposition in the brains of transgenic mouse models.46,47⇓

As was true in our previous analysis of prevalence data from Cache County,21 we found no evidence that the inverse association of NSAID and AD varied with APOE genotype. To our knowledge, in fact, no study has suggested a strong influence of APOE genotype on this relationship. We did, however, find suggestive evidence that the association between NSAID and AD varies with age. One previous study reported a stronger apparent effect of NSAID in those younger than 85,24 and another study reported a similar association between age and a possible AD-protective effect of statin use.48 The current results are no more than suggestive, however, and more investigation is needed.

In what we believe to be the first prospective study to examine another question, we found no evidence that current use of H2RA is associated with incidence of AD. These results are at odds with those from earlier retrospective and cross-sectional investigations, including our own.8,21,31⇓⇓ We have no direct explanation for the discrepancy but wonder about the declining use of H2RA (and, especially, of potent prescription formulations) in recent years, as these agents have been largely supplanted by proton pump inhibitors. Such declining use was presumably responsible for our observation that very small numbers of Cache County subjects had used H2RA for periods extending several years prior to the Wave I interview. These small numbers precluded meaningful analyses of the relation between extended former use and incident AD—exactly the sort of analyses that were needed here to clarify the apparent effect with NSAID. If we are correct, the opportunity for new observational studies relating H2RA use and incident AD may be behind us.

Among its strengths, this new investigation in the Cache County Study attempted to follow an entire population (not a sample). Response rates were high, thus reducing the threat of selection bias. The large size of the study enabled us to test several a priori hypotheses with reasonable statistical power while controlling for important potential confounders. Prospective studies such as this one can avoid two important limitations of cross-sectional designs. First, they classify exposures from data collected at a time when participants, having been effectively screened for dementia, should be able to provide more reliable information about their current and former use of NSAID, including use of OTC formulations not typically available from other sources. Second, analysis of incidence data mitigates the so-called prevalence case bias in which exposures that are associated with altered survival after onset of illness may be mistaken for those that alter incidence.

Our study has several limitations, however. We ascertained exposures to the six classes of medicines by self-report at the initial contact, and the period of follow-up was only 3 years. Individuals who developed AD during this relatively brief interval may have already begun experiencing cognitive impairment at the time of their initial contact, thus promoting their selective failure to recall prior medication use, especially former use dating back >2 years previously. We suggest that this is not a likely explanation of our findings with NSAID, however, because similar inverse associations were not observed with any of the “control” medications when we examined their lifetime use or former versus current use (data not shown). It seems difficult to explain why participants should selectively under-report the former use of NSAID but not these other medications. Nonaspirin, non-NSAID analgesics, in particular, are typically used for many of the same indications as OTC NSAID and therefore should be vulnerable to the same reporting biases. The relevant difference, we suggest, is that these other analgesics do not inhibit COX.

We also note that this study was conducted in a relatively homogeneous population with unusual sociocultural attributes. Over 90% of the population in Cache County are members of the Church of Jesus Chris of Latter-Day Saints and therefore tend not to use tobacco or alcohol. They are also relatively highly educated and have access to quality health care. Probably as a result, they have unusually low rates of chronic disease and long life expectancy.32 Although we have no reason to believe that such characteristics influence the relation of NSAID use and AD, it is certainly possible that our findings would not generalize to other populations.

In the end, the only sure way to demonstrate whether NSAID can delay or prevent the onset of AD is to conduct randomized prevention trials. Our findings suggest that several years of observation may be required before significant differences would likely emerge in such trials between NSAID-treated and placebo-treated groups. As we have suggested recently in relation to similar findings with postmenopausal hormone replacement therapy (Zandi et al., submitted for publication),49 caution may be in order when interpreting early results from such trials, and patience may be rewarded only in the long run.

Other Cache County Study investigators

James Burke, MD, Michelle Carlson, PhD, Chris Corcoran, PhD, Marion David, PhD, Robert Green, MD, Andrea Hart, MS, Michael Helms, MS, Carol Leslie, MA, Constantine Lyketsos, MD, Richard A. Miech, PhD, Maria Norton, PhD, Brenda Plassman, PhD, Christine Reagan, MS, Ingmar Skoog, MD, David C. Steffens, MD, Martin Steinberg, MD, JoAnn T. Tschanz, PhD, Jeannette J. Townsend, MD, Kathleen A. Welsh-Bohmer, PhD, Nancy West, MS, Michael Williams, MD, and Bonita W. Wyse, PhD.

Acknowledgments

Supported by NIH grant AG-11380 and by MH-14592 (Dr. Zandi).

Acknowledgment

The authors thank the Neurogenetics Laboratory of the Bryan AD Research Center at Duke University for the APOE genotyping and Tony Calvert, RN, Barb Gau, MSW, Tiffany Newman, BS, Cara Brewer, BS, Russell Ray, MS, and Joslin Werstak, BA, for expert technical assistance.

Footnotes

  • *See the Appendix for a list of Study members.

  • Received November 4, 2001.
  • Accepted June 11, 2002.

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