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High-Sensitivity C-Reactive Protein and Cognitive Function in Older Women

Weuve, Jennifer*†; Ridker, Paul M.‡§¶; Cook, Nancy R.‡∥; Buring, Julie E.*,**; Grodstein, Francine†,††

doi: 10.1097/01.ede.0000198183.60572.c9
Original Article
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Background: Inflammatory processes may be involved in the development of dementia, although findings from epidemiologic studies directly examining inflammatory markers and dementia or its precursor, impaired cognitive function, are inconsistent.

Methods: We measured plasma levels of the inflammatory marker, C-reactive protein, using a high-sensitivity assay (hs-CRP) in 4231 older participants of the Women's Health Study, who provided blood samples between 1992 and 1996 when they were age 60 to 90 years. From 1998 to 2000, we administered a battery of 5 cognitive tests measuring general cognition, verbal memory, and category fluency. Using multiple linear regression, we compared mean cognitive test scores across quintiles of hs-CRP, adjusting for potential confounding factors.

Results: There was a wide distribution of hs-CRP levels among these women, and a large proportion had levels considered to reflect a high risk of cardiovascular disease. We observed no suggestion, however, that higher hs-CRP levels were associated with poorer cognitive performance. For example, on a global score combining results of all the cognitive tests, mean scores among women in the highest quintile of hs-CRP did not differ from those in the lowest quintile (multivariable-adjusted mean difference = 0.04; 95% confidence interval [CI]: −0.02 to 0.11, P for trend across quintiles = 0.38).

Conclusion: Overall, in these women, we found no evidence of a link between hs-CRP, a marker of inflammation, and decrements in cognitive function.

From the *Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; the †Department of Epidemiology, Harvard School of Public Health, Boston, MA; ‡Brigham and Women's Hospital, Center for Cardiovascular Disease Prevention, Boston, MA; the §Division of Cardiology, Brigham and Women's Hospital, Boston, MA; ¶Harvard Medical School, Donald W. Reynolds Center for Cardiovascular Research, Boston, MA; the ∥Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Leducq Center for Molecular and Genetic Epidemiology, Boston, MA; the **Department of Ambulatory Care and Prevention, Harvard Medical School, Boston, MA; and the ††Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Channing Laboratory, Boston, MA.

Submitted 18 April 2005; accepted 23 September 2005.

Dr. Weuve was partially supported by NIA training grant AG000158. The work described in this paper was supported by grants AG15424 and CA87969 from the National Institutes of Health. Dr. Ridker is listed as a coinventor on patents held by the Brigham and Women's Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease.

Dr. Weuve is now at the Harvard School of Public Health, Department of Environmental Health, Boston, MA.

Correspondence: Jennifer Weuve, Harvard School of Public Health, Department of Environmental Health, Landmark Center, 3rd Floor East, 401 Park Drive, Boston, MA 02215. E-mail: jweuve@hsph.harvard.edu.

Agrowing body of research implicates inflammatory processes in the development of dementia.1 Many indications of inflammation have been identified in the brains of those with Alzheimer disease (AD), including activated microglia, astrocytes, and elevations in complement and inflammatory cytokines.1 In addition, chronic low-grade elevations in inflammatory reactants independently predict cardiovascular disease2,3; dementia and cardiovascular disease appear to share many risk factors,4 thus also suggesting a possible link between inflammation and dementia. Some epidemiologic studies of dementia have reported associations with serum levels of inflammatory markers,5–7 but results are not consistent.8,9 In addition, although several epidemiologic studies have reported associations between antiinflammatory agents and dementia,10,11 therapeutic trials have not shown these agents to be effective at halting the progression of AD.12,13 These findings have led to the suggestion that inflammation may be more important earlier than later in the disease process.

Studies of early cognitive decline, a likely indicator of preclinical dementia,14,15 offer the potential to explore whether inflammation may play an early role in the development of dementia. Yet, studies of cognition, too, have reported both positive7,16–20 and null7,16,17,19–21 findings for a variety of inflammatory markers, although only a few of these investigations have been large in scale.

We examined the relation between plasma high-sensitivity C-reactive protein (hs-CRP) levels and cognitive function among a large group of over 4000 older, community-dwelling women from the Women's Health Study.

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METHODS

The Women's Heath Study (WHS) was a randomized, double-blind, placebo-controlled 2 × 2 factorial trial testing the benefits and risks of low-dose aspirin (100 mg every other day) and vitamin E (600 IU every other day) in the prevention of cardiovascular disease and cancer.22 From 1992 through 1996, 39,876 female health professionals, age 45 years and older, were randomized to one of the 4 treatment groups. Eligible women had no history of cardiovascular disease, cerebrovascular disease, cancer (except nonmelanoma skin cancer), or other major chronic illness. Seventy-one percent of the participants provided blood samples before randomization. We contacted participants annually with a mailed questionnaire that updated information on individual health characteristics, behaviors, and outcomes. Ninety-three percent of women returned a mailed questionnaire at the 5-year follow up, reflecting high continued participation. This study was approved by the Institutional Review Board of Brigham and Women's Hospital (Boston, MA). All study participants gave written informed consent to participate in the WHS.

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Population for Analysis

From 1998 to 2000, 4.4 to 7.8 years after blood draw, telephone assessments of cognitive function were conducted among the older WHS participants. Women eligible to participate in the study of cognitive function were age 66 years and older as of 1998. Of 7107 women whom we attempted to contact for cognitive testing, 5.7% refused to participate and 4.1% were unreachable (ie, no telephone number could be located). In total, 6314 women completed the cognitive assessment, and 4586 of these had provided blood samples. Orally administered estrogens raise CRP,23–25 so we excluded the 3% of women who did not report their hormone use at enrollment because we were unable to account for their hormone use in these analyses. We also excluded the 5% of women whose CRP levels, measured by a high-sensitivity assay (hs-CRP), were indicative of an acute inflammatory response (hs-CRP >15 mg/L). Thus, these analyses are based on 4231 participants.

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Ascertainment of C-Reactive Protein

Before randomization to the study agents, women provided blood samples in EDTA-containing tubes, which were then centrifuged and stored in liquid nitrogen freezers (−180°C). As part of a study of hs-CRP and heart disease in all participants who provided blood,3 samples were thawed and then assayed at a core laboratory facility using a validated, high-sensitivity assay (Denka Seiken, Tokyo, Japan).26 We evaluated assay precision using approximately 5% of specimens: blinded, duplicate blood samples were analyzed on 5 different days, and the resulting coefficients of variation were low and varied from 2.2% to 6.1% for CRP concentrations ranging from 0.15 to 1.90 mg/L.27

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Cognitive Function Assessment

Cognitive function was determined by telephone interviews. The cognitive assessment contained 5 component tests.

To test general cognition, we administered the Telephone Interview for Cognitive Status,28 which contains items on orientation, immediate verbal recall, registration, opposites, current events, serial subtraction, counting, and other skills. Brandt et al28 reported high test–retest reliability and a strong linear correlation between scores on the Telephone Interview for Cognitive Status and Mini-Mental State Examination (Pearson correlation = 0.94).

To test verbal memory, we administered the East Boston Memory Test,29 which assesses immediate and delayed paragraph recall. Scores on this pair of tests correlate with the Wechsler Memory Scale–Revised Logical Memory subtests,30 which have been shown to identify demented patients when administered repeatedly over time.31 As an additional test of delayed verbal memory, we also administered a delayed recall of the 10-word list from the Telephone Interview for Cognitive Status. Finally, the fifth component test was of category fluency,32 in which women were asked to name as many animals as they could during a 1-minute interval.

To summarize women's performance on these tests, we computed a global score that combines results from the Telephone Interview for Cognitive Status, the immediate and delayed recalls of the East Boston Memory Test, the delayed recall of the 10-word list, and the test of category fluency. We calculated the global score by averaging the z scores from the 5 cognitive tests. Such a composite score is commonly used in cognitive studies to estimate overall function,15,33 because it integrates information from a variety of sources and thus provides a more stable representation of cognitive function than a single test.

We have evaluated the reliability and validity of our telephone cognitive battery in high-functioning women. An interinterviewer reliability study demonstrated high consistency (correlation >0.95 for each test) across interviewers in scoring cognitive assessments of 21 WHS participants. We tested the reliability of the Telephone Interview for Cognitive Status by interviewing 35 women from our Nurses’ Health Study (of similar age and educational status as the WHS Cognitive Study participants) twice, 31 days apart; the scores from the 2 interviews were highly correlated (test–retest correlation = 0.7). In a study we conducted among 61 nuns from the Rush Religious Orders Study, also similar in age and educational status to the WHS Cognitive Study participants, global scores from our brief telephone-administered cognitive assessment correlated highly with global scores from in-person interviews composed of a battery of 21 tests (r = 0.81), attesting to the validity of our telephone method for assessing cognitive function.

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Statistical Analysis

We separately examined each of the 5 tests included in our cognitive function assessment and the global score. We used multiple linear regression to compare mean cognitive function scores across quintiles of hs-CRP, adjusting for the variables described subsequently. All potential confounding and intermediate variables were identified at the time of the blood collection through the self-reported questionnaires, except for lipid levels, which we measured in the women's blood samples.

We constructed 3 sets of regression models. In the first set (“set 1”), we included factors that account for much of the variance in cognitive scores: age at interview, educational attainment (licensed practical nurse or licensed vocational nurse, 2-year registered nurse diploma, 3-year registered nurse diploma, bachelor's degree, master's degree, doctoral degree), household income (<$10,000, $10,000–19,999, $20,000–29,999, $30,000–39,999, $40,000–49,999, $50,000–99,999, >$100,000, unknown), and timespan between blood draw and cognitive assessment. In the second set of models (“set 2”), we added factors that are correlated with hs-CRP levels as well as cognitive function: alcohol consumption (rarely/never, 1–3 drinks/mo, 1–6 drinks/wk, ≥1 drink/d), history of hypertension (yes, no), body mass index (continuous), frequency of strenuous physical activity (rarely or never, <once/wk, 1–3 times/wk, 4 or more times/wk), cigarette smoking (current, past, never), postmenopausal hormone use (unopposed estrogen, estrogen with progestin, past use/never use), the ratio of total plasma cholesterol to high-density lipoprotein cholesterol (in quartiles), and plasma triglyceride level (in quartiles). The third set of models also included 2 potential intermediates between CRP and cognition, type 2 diabetes and myocardial infarction, self-reported after blood draw.

We computed tests of linear trend by fitting models with an ordinal term, which took on the values of each hs-CRP quintile (ie, 1, 2, 3, 4, and 5).

Orally administered estrogens induce a marked upward shift in hs-CRP levels, an effect that subsides after these hormones are discontinued.23–25,34,35 In our data, hs-CRP levels were, on average, 57% greater among oral estrogen users than among nonusers. We were concerned that simply combining estrogen users and nonusers in the analysis would result in an artificially extreme concentration of estrogen users in the highest quintile of hs-CRP and thus produce biased results. Therefore, we defined separate hs-CRP quintile cut points for nonusers and users of oral estrogen. The distribution of hs-CRP levels among nonusers of oral estrogen was similar to those observed in other general population studies.26,36 Quintiles of hs-CRP, in milligrams per liter, for our subjects were: <0.69, 0.69 to 1.38, 1.39 to 2.35, 2.36 to 4.12, and >4.12. Thus, approximately half of the fourth quintile and all of the fifth quintile encompassed hs-CRP levels determined to be predictive of high CVD risk (>3 mg/L, according to the Centers for Disease Control and Prevention and the American Heart Association37). Quintiles of hs-CRP among oral estrogen users, who comprised 35% of our study sample, were: <1.31, 1.31 to 2.49, 2.50 to 3.72, 3.73 to 5.80, and >5.80 mg/L. We also conducted several alternative analyses. In one, we analyzed the data stratified by hormone use. In another, we calculated quintiles of hs-CRP based on the entire study population (ie, combining users and nonusers of oral estrogens) and then adjusted for hormone use in our regression models.

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RESULTS

Compared with women in the lowest hs-CRP quintile, women with higher levels of hs-CRP appeared somewhat less healthy (Table 1). They were more likely to be current smokers and less likely to regularly engage in physical activity. They also had a higher mean body mass index and were more likely to have a history of hypertension and diabetes.

TABLE 1

TABLE 1

Importantly, the associations between both age and education (2 of the best-established risk factors for cognitive impairment) and cognition were similar to those observed among comparable study populations. For example, in this study, the mean difference in the global score associated with a 1-year increment in age was −0.038 standard units (95% confidence interval [CI] = −0.043 to −0.034), as compared with −0.045 (−0.049 to −0.041) among participants in the Nurses’ Health Study, another population of female health professionals. Similarly, in the Women's Health Study, women with a bachelor's degree had mean global scores that were 0.076 units greater (0.026–0.127) than those among women with a 3-year registered nurse diploma; this was consistent with the mean difference of 0.060 units (0.060–0.113) found in the Nurses’ Health Study.

We found that unadjusted mean cognitive function scores did not vary by quintile of hs-CRP (Table 2). Only on the test of category fluency was there a tendency for poorer performance with increasing hs-CRP level.

TABLE 2

TABLE 2

Overall, after adjustment for potential confounding factors, we did not observe an association between hs-CRP levels and cognitive performance (Table 3). On the global score, for example, the multivariable-adjusted mean difference between those in the top compared with the bottom quintile of hs-CRP was 0.04 (95% CI = −0.02 to 0.11, P for trend across quintiles = 0.38). Similarly, on each of the individual tests, we did not find that there was increasingly poorer performance with increasing level of hs-CRP (range of P for trend across these tests = 0.05–0.99). Further adjustment for type 2 diabetes and myocardial infarction (possible intermediate variables) after blood draw did not alter these results.

TABLE 3

TABLE 3

We also examined interactions between CRP and several variables (data not shown). Because half of the women in this study were assigned to very low-dose aspirin treatment (100 mg every other day) or to vitamin E (600 IU every other day) after providing their blood sample, we may not have been able to detect effects of inflammation on cognition if aspirin or vitamin E treatment resolved any chronic inflammatory issues.38 Although it is unlikely that very low-dose aspirin2 or moderate-dose vitamin E38,39 meaningfully affects inflammation, we reevaluated the association between CRP and cognitive function, stratifying by treatment assignment, and in none of the treatment groups did we find evidence of such an association.

In addition, we examined interactions of hs-CRP with age, education, history of hypertension, low-density lipoprotein cholesterol, the ratio of total cholesterol to high-density lipoprotein cholesterol, and myocardial infarction (although there were few cases of myocardial infarction among these generally healthy women). We found no evidence, however, of interactions between hs-CRP and any of these variables. We also separately analyzed the data from women who were not using oral estrogen, and those who were using oral estrogen at the time of blood draw, and the results in these 2 strata were similar. In addition, analyses in which we defined quintiles of hs-CRP without regard to oral estrogen use, and adjusted for hormone therapy in the model, also indicated no association between hs-CRP and performance on the cognitive tests.

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DISCUSSION

In this study of 4231 older women, hs-CRP level was not associated with cognitive function. Few other large-scale epidemiologic studies have examined the relation between inflammatory markers and cognitive function, but their findings for CRP are generally consistent with ours. Most recently, researchers for the Longitudinal Aging Study Amsterdam evaluated 1284 adults, age 62 to 85 years, and found no association between serum levels of 4 inflammatory proteins—α1-antichymotrypsin, CRP, interleukin-6 (IL-6), and albumin—and baseline performance on 5 cognitive tests.20 Three years later, elevated α1-antichymotrypsin at baseline was associated with a modest increase in the risk of decline in performance on 3 of the tests and was significantly associated with risk of decline on the Mini-Mental State Examination (odds ratio = 1.60; 95% CI = 1.05–2.43 for the top vs the bottom tertile). Nonetheless, the other inflammatory markers were not associated with risk of decline on any of the tests. In the Health, Aging, and Body Composition study (HealthABC),19 among 3031 adults age 70 to 79 years, there was no association between CRP, IL-6, or tumor necrosis factor-α (TNF-α) and baseline performance on the modified Mini-Mental State Examination. Two years later, modified Mini-Mental State Examination scores were only slightly lower among those with higher CRP (mean score = 86.2 vs 87.2 in the top vs bottom tertile; P = 0.05) with little association between CRP and risk of cognitive decline (relative risk = 1.24; 95% CI = 0.96–1.63 for the top vs bottom tertile); results were somewhat stronger for IL-6. In a subsequent investigation of 2632 individuals from this study, elevated serum levels of inflammatory markers were associated with the risk of cognitive decline only in combination with metabolic syndrome (P for interaction = 0.03).40 Similarly, in the Leiden 85-Plus Study, with 553 participants, a “proinflammatory profile” was designated as the ratio of TNF-α to IL-10; overall, there was no association between inflammation and cognition. However, among those with cardiovascular disease, a “proinflammatory profile” was inversely associated with performance on 5 tests of cognitive function (P < 0.05 for all tests; P for interaction < 0.04 for 4 of 5 tests).7 We found no interactions between CRP and heart disease, hypercholesterolemia, or hypertension, although our cohort was generally healthier than either the HealthABC or Leiden 85-Plus cohorts. The strongest relations were found in the MacArthur Studies of Aging, where researchers investigated serum IL-6: those in the highest tertile were about twice as likely as those in the lowest tertile to decline over the ensuing 2.5 and 7 years on a summary test of recognition, recall, and spatial perception (95% CI = 1.30–3.19 at 2.5 years, 1.14–3.18 at 7 years).18 As a result of the particular interest in CRP levels as an important predictor of heart disease, hs-CRP was measured in nearly all of our WHS participants for an investigation of CRP and heart disease; unfortunately, we did not have comparable data for other inflammatory markers such as IL-6, and thus we could not examine those relations.

Overall, there is not consistent evidence in the epidemiologic literature that inflammatory markers predict cognitive status, and it remains possible that inflammation does not play an independent, early role in the pathogenesis of dementia. Breitner and Zandi41 have pointed out that, even in studies reporting an inverse association between use of nonsteroidal antiinflammatory drugs (NSAIDs) and cognitive decline or dementia, the NSAID dose is generally too low to result in substantial antiinflammatory effects; thus, possible neuroprotective effects of NSAIDs may indeed be unrelated to inflammation. In vitro data on various NSAID agents supports this hypothesis in that some, but not all, antiinflammatory medications inhibit amyloid-β synthesis.42

There are limitations to our study. First, like in all observational studies, confounding by measured or unmeasured factors is possible. Confounding is likely minimized, however, in this homogeneous cohort of health professionals, and adjustment for a wide variety of potential confounding factors did not alter our results substantially. In particular, women who had higher levels of hs-CRP were more likely to show signs of relatively poor health (eg, diabetes, hypertension), suggesting that the most likely confounding bias would have led us to overestimate harm associated with elevated hs-CRP and, thus, could not explain the observed lack of an association.

Second, we were unable to include in our study 1687 women who did not provide a blood sample. However, characteristics of women in the cognitive study who did and did not provide blood samples were similar. For example, their mean difference in age was only 4 months; among those who provided blood samples, 38% had a bachelor's degree or higher, and their mean body mass index was 25.6 kg/m2, as compared with those who did not provide blood samples, among whom 31% had a bachelor's degree or higher and the mean body mass index was 25.8 kg/m2. There is little potential for bias arising from these minimal differences between women who did and did not provide blood samples.43

It is possible that nondifferential error in the measurement of CRP biased our results toward the null, although we established high precision for the hs-CRP measures. In addition, random assignment to aspirin and vitamin E after blood draw could have lowered inflammation in the interim, effectively increasing the random misclassification in our hs-CRP measurement. However, as we have stated previously, the doses are likely too low to induce meaningful antiinflammatory effects. Moreover, we found no relation between hs-CRP level and cognition after stratifying by treatment assignment. Furthermore, studies in these same subjects were instrumental in establishing strong associations between hs-CRP and cardiovascular disease,3 in addition to hypertension44 and type 2 diabetes45; thus, it is clear that treatment assignment does not obscure our ability to detect important relations between inflammation and chronic diseases in this cohort.

Additionally, our telephone method of assessing cognition may limit our ability to detect risk factor relations. However, we have established high validity of our telephone method against in-person cognitive assessments. In addition, we have detected strong associations, in this cohort and in another similar cohort of female health professionals, between numerous established risk factors and lower cognitive function,46–48 establishing our ability to identify risk factors for impaired cognition. Finally, single assessments of cognitive function do not capture cognitive change. However, the women were largely in their early 60s when they provided blood samples, and the cognitive testing was conducted 4.4 to 7.8 years later. Thus, “reverse causation” is less likely here than in a typical cross-sectional study. Additionally, with this long follow up, our one-time assessments likely at least partly reflect changes in cognitive function that have occurred since hs-CRP was measured. Nonetheless, because directly measuring change in cognition is clearly important, we are continuing to follow the women and will eventually be able to examine the relation of hs-CRP to cognitive decline over time.

It is possible that the results of our study, conducted among a population of relatively healthy older women, do not generalize to other older adults. Yet the range of hs-CRP in our population was similar to that observed in other general population studies,26,36 and, as we have described, in these same women, we identified strong relations between hs-CRP and several other chronic diseases.

In conclusion, the role of inflammation in dementia development continues to be controversial. Our data suggest that, in older adults, levels of an important inflammatory marker, C-reactive protein, are not related to cognitive function, a probable marker of dementia in its earliest stages.14,15 Further investigation of this and other inflammatory markers, and their role at various stages in the dementia process, will help to better clarify any relations.

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ACKNOWLEDGMENTS

We are indebted to the participants in the Women's Health Study who collaborated with us in this study of cognitive function.

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