Hypertension and cognitive impairment are two common

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1 A Prospective Study of the Effect of Hypertension and Baseline Blood Pressure on Cognitive Decline and Dementia in Postmenopausal Women: The Women s Health Initiative Memory Study Karen C. Johnson, MD, MPH, Karen L. Margolis, MD, MPH, w Mark A. Espeland, PhD, z Christopher C. Colenda, MD, Howard Fillit, MD, k JoAnn E. Manson, MD, DrPH, # Kamal H. Masaki, MD, Charles P. Mouton, MD, MS, ww Ronald Prineas, MD, PhD, z Jennifer G. Robinson, MD, MPH, zz and Sylvia Wassertheil-Smoller, PhD, for the Women s Health Initiative Memory Study and Women s Health Initiative Investigators OBJECTIVES: To examine the relationship between baseline hypertension, blood pressure, and the development of cognitive decline in participants in the Women s Health Initiative Memory Study (WHIMS). DESIGN: Prospective analyses. SETTING: Thirty-nine centers. PARTICIPANTS: Seven thousand one hundred forty-nine women aged 65 and older. MEASUREMENTS: The Modified Mini-Mental State Examination (3MS) was used to assess global cognitive functioning. Participants who scored below pre-established cutpoints were scheduled for more-extensive neurocognitive assessments. Results from these assessments were centrally adjudicated. RESULTS: The mean age of this group of 7,149 participants at baseline was , and the mean 3MS score was During a mean follow-up period of 4.5 years, women without hypertension tended to have slightly higher 3MS scores than women with hypertension (P 5.001), but the difference was not seen after adjustment for covariates (P 5.17). Women with hypertension also appeared to be at greater risk for probable dementia or mild cognitive impairment (MCI) (hazard ratio , 95% confidence interval , P 5.01), although when potential cofounders were accounted for, this association was no longer significant (P 5.06). CONCLUSION: Hypertension and high blood pressure at baseline were not independently associated with MCI or probable dementia over time in older, cognitively intact, postmenopausal women enrolled in WHIMS after other potential confounders were taken into account. These analyses should not be viewed as discouraging appropriate medical treatment for hypertension. J Am Geriatr Soc 56: , Key words: women s health; hypertension; cognition; dementia; blood pressure From the Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, Tennessee; w Berman Center for Outcomes and Clinical Research, Hennepin County Medical Center, Minneapolis, Minnesota; z Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina; Health Science Center, Texas A&M University, College Station, Texas; k Institute for the Study of Aging, New York, New York; # Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts; Department of Geriatric Medicine, University of Hawaii, Honolulu, Hawaii; ww Department of Family and Community Medicine, University of Texas Health Science Center, San Antonio, Texas; zz Departments of Epidemiology and Medicine, University of Iowa, Iowa City, Iowa; and Albert Einstein College of Medicine, Bronx, New York. Address correspondence to Karen C. Johnson, MD, MPH, Department of Preventive Medicine, University of Tennessee Health Science Center, 66 N. Pauline, Suite 633, Memphis, TN Kjohnson@utmem.edu DOI: /j x Hypertension and cognitive impairment are two common chronic conditions associated with the aging process. 1 The National Center for Health Statistics estimates that the prevalence of hypertension in women aged 65 to 74 is 73.4%. 2 In the United States and Europe, dementia affects 3.6% to 10.3% of the population aged 65 and older, with vascular dementia estimated to be responsible for 10% to 20% of all dementia cases. 3 6 Alzheimer s disease affects an estimated 4 million Americans. 7 The prevalence of age-associated memory impairment in the general older population is estimated to be 17% to 34% JAGS 56: , 2008 r 2008, Copyright the Authors Journal compilation r 2008, The American Geriatrics Society /08/$15.00

2 1450 JOHNSON ET AL. AUGUST 2008 VOL. 56, NO. 8 JAGS The relationship between hypertension and cognitive function has been examined in a number of cross-sectional and longitudinal studies. Although results from these studies have been inconsistent, some prospective observational studies of blood pressure (BP) and cognitive function have found an association between hypertension and decline in cognitive function and development of dementia years later Several prospective observational studies have also suggested that antihypertensive treatment may be associated with lower risk of the development of cognitive impairment and dementia in elderly people These observations have prompted evaluations of the efficacy of antihypertensive medication on cognitive impairment in several randomized, placebo-controlled, clinical trials, but these studies have also shown mixed results, with two showing no difference in overall cognitive function or incident dementia, one trial showing lower risk of cognitive decline and dementia only in subjects with recurrent stroke, 24 and one trial showing an overall significant reduction in the incidence of dementia. 25 Addressing these inconsistencies requires a careful exploration of the relationships between BP and cognitive function while controlling for potential confounders that may affect the association. Using data from the Women s Health Initiative (WHI) Hormone Trial (HT) and the Women s Health Initiative Memory Study (WHIMS), analyses were performed to examine the effects of hypertension, antihypertensive treatment, and baseline BP on cognitive function and on the incidence of probable dementia. METHODS WHI is a large, multicenter investigation of postmenopausal women aged 50 to 79 who are enrolled in the clinical trials of Hormone Therapy, Diet Modification or Calcium Vitamin D or the Observational Study. 26 The study design, eligibility criteria, and recruitment procedures of the WHI HT have been described elsewhere Key exclusion criteria for participation in the WHI HT were invasive cancer within the previous 10 years, major cardiovascular (myocardial infarction or stroke) disease events in the previous 6 months and medical conditions contraindicating for hormone therapy. Women with systolic BP (SBP) greater than 200 mmhg or diastolic BP (DBP) greater than 105 mmhg were also excluded from the WHI clinical trials. In the WHI HT, women with a uterus at baseline were randomized with equal probability to receive mg of conjugated equine estrogens with 2.5 mg medroxyprogesterone acetate (PremPro, Wyeth Pharmaceuticals, Inc., St. Davids, PA) or a matching placebo (E1P trial) per day. Women without a uterus at baseline were randomized with equal probability to receive mg of conjugated equine estrogens (Premarin, Wyeth Pharmaceuticals, Inc.) or a matching placebo (E-Alone trial) per day. After discovery of an unfavorable risk-to-benefit ratio, the WHI E1P trial was stopped early for harm (July 2002). 30 The WHI E-Alone trial was also stopped early for harm because of a greater risk of stroke and a lack of benefit for coronary heart disease (February 2004). 31 WHIMS 29 is an ancillary study to the WHI HT. 26,32 WHIMS was conducted to assess the relative effect of estrogen alone or in combination with a progestin on the incidence of dementia and global cognitive functioning in postmenopausal women. The decisions to stop the WHI HT also ended WHIMS Participants in the WHIMS trials were recruited between May 1996 and December 1999 from women in the WHI HT who were aged 65 and older and free of dementia as ascertained according to the WHIMS protocol. 29 Written informed consent was obtained. The National Institutes of Health and institutional review boards at each clinical site approved the protocol and consent forms. A detailed description of the WHIMS protocol for detecting probable dementia and mild cognitive impairment has been published. 29 Global cognitive function was measured using the Modified Mini-Mental State Examination (3MS) 37 at baseline and annually for up to 8 years. The 3MS consists of 15 items that sum to 0 to 100, with higher scores reflecting better cognitive functioning. The 3MS has good reliability, sensitivity, and specificity for detecting cognitive impairment and dementia. 38,39 Trained and certified technicians who were masked to treatment assignment administered the 3MS. Participants who scored below pre-established cutpoints 33 were scheduled for a moreextensive neurocognitive assessment and neuropsychiatric examination. Data from this testing were then centrally adjudicated. 29 Only 3MS data collected during the WHI HTwere used in this analysis. Any 3MS data collected after July 8, 2002 (E1P trial) and February 28, 2004 (E-Alone trial) were excluded. At baseline, certified staff in the WHI clinic measured BP using standardized procedures. The average of two baseline readings taken at the same clinic visit was used for these analyses, and hypertension at baseline was defined as a self-report of current drug therapy for hypertension or clinic measurement of SBP of 140 mmhg or higher or DBP of 90 mmhg or higher at enrollment. Within the category of women with hypertension, three categories defined according to current drug treatment and BP control at baseline were further created. Postbaseline BP measurements were not included in the analyses. Antihypertensive drug therapy was established by reviewing original medication bottles at screening and after 1, 3, and 6 years of follow-up. The name of the medication on the label was entered into the study database and matched to the corresponding item in a pharmacy database: the Master Drug Data Base (Medi-Span, Indianapolis, IN). Antihypertensive medications were classified as diuretic, beta-blocker, calcium-channel blocker, angiotensinconverting enzyme (ACE) inhibitor, other monotherapy, or combination therapy. More than 85% of women who selfreported on the enrollment questionnaire that they were taking medication for hypertension provided medications at their baseline visit that fell into one of these drug class categories. 40 Baseline demographic data and medical histories were collected using self-report. Cardiovascular disease (CVD) history was coded as positive if the participant reported a history of myocardial infarction, stroke, angina pectoris, coronary bypass surgery, or angioplasty of coronary arteries at their baseline visit. Covariates included in the analyses were those found to be significantly related to 3MS scores 34,36 and that may be expected to be associated with

3 JAGS AUGUST 2008 VOL. 56, NO. 8 WOMEN S HEALTH, HYPERTENSION AND COGNITIVE FUNCTION 1451 hypertension or BP control or cognition and included age group, education, ethnicity, smoking status, alcohol intake, body mass index (BMI), physical activity (metabolic equivalents per week), self-report of current treatment for hypercholesterolemia, history of CVD, history of diabetes mellitus, use of aspirin, prior use of hormone therapy, depressive symptoms (Center for Epidemiologic Studies Depression Scale score 0.60), and WHI HT intervention assignment. Statistical Analysis For these analyses, data from the WHI HT and WHIMS were used to assess relationships between hypertension and its treatment and 3MS scores at baseline and during followup in the 7,149 WHIMS participants (96.1% of the 7,479 original WHIMS cohort). Sixty-seven WHIMS participants were excluded from this analysis, because they did not have a baseline 3MS; 260 were excluded because they did not have a follow-up 3MS; and three were excluded because baseline hypertension status could not be established. Differences in baseline factors in women grouped according to baseline hypertension status were assessed using chi-square tests and analyses of variance. Cross-sectional analyses of associations between 3MS scores and hypertension and BP characteristics were examined using analyses of variance and covariance. To assess associations between baseline hypertension status and changes in cognition over time, generalized linear models were used to contrast mean 3MS scores collected during follow-up with adjustment for baseline 3MS and WHI HT treatment assignment. A first-order autocorrelation structure was assumed for repeated measures; models were fitted using maximum likelihood and contrasted using Wald tests (SAS Institute, Inc., Cary, NC). Associations between baseline hypertension treatment and baseline BP control (o140/90 vs 140/90 mmhg) and incidence of probable dementia and a composite endpoint of probable dementia or mild cognitive impairment (MCI) were examined using proportional hazards regression models and cumulative hazard. The time to these events was assigned as the number of days from enrollment to the date of the 3MS that triggered further evaluation of cognitive impairment. In these analyses, women were censored when they were lost to follow-up or at their trial s termination. Analyses are reported with time measured from randomization and age group as a covariate, but because this approach may sometimes introduce biases, they were repeated with the timescale corresponding to age. 41 RESULTS Table 1 describes characteristics of the WHIMS cohort at baseline. The following factors were associated with higher average 3MS scores: younger age, white ethnicity, higher formal education, lower BMI, greater physical activity, no treatment for hypercholesterolemia, no diabetes mellitus, past smoking, no depressive symptoms, consumption of alcohol, regular use of aspirin, and no history of CVD. Hypertension was more frequent in women with the following characteristics: older age, African-American ethnicity, lower formal education, greater BMI, less physical activity, treatment for hypercholesterolemia, diabetes mellitus, no current alcohol intake, regular use of aspirin, and a history of CVD. Hypertension was more prevalent and 3MS scores were lower in the E-alone WHIMS trial participants than in the women enrolled in the E1P WHIMS trial. The prevalence of hypertension at baseline was higher in women assigned to placebo than to active therapy in the E-Alone WHIMS trial. Baseline mean 3MS scores (Table 2) were slightly higher in women without hypertension than in those with hypertension, although adjustment for covariates attenuated this difference, reducing it to nonsignificance (P 5.13). In the unadjusted models, the level of SBP and pulse pressure were associated in an inverse fashion with baseline mean 3MS scores, although these relationships did not remain statistically significant after covariate adjustment. Because the model adjusting for only age group, ethnicity, and education showed nearly identical results compared with those from the full covariate-adjusted model, the remaining tables will show only results from the demographic covariate adjusted model found in Table 2. Follow-up rates for 3MS were 97.5% (Year 1), 92.6% (Year 2), 91.6% (Year 3), 86.1% (Year 4), and 97.7% (thereafter). During follow-up, women who did not report a history of hypertension or had controlled BP had higher 3MS scores than women with a history of hypertension or uncontrolled BP (Table 3), although adjustment for covariates eliminated all of these differences. Class of antihypertensive medication used was not associated with change in 3MS during follow-up. In women not currently taking an antihypertensive medication, those whose DBPs were between 60 and 89 mmhg had higher 3MS scores than women with lower or higher DBPs. After adjustment, only women with lower DBP (o60 mmhg) had lower 3MS scores. (Po.001). In women taking an antihypertensive medication, DBP was not associated with 3MS score. Women with the highest SPB and pulse pressures had the lowest mean 3MS scores. This relationship was strongest for pulse pressures in women currently taking an antihypertensive medication, remaining statistically significant after covariate adjustment (P 5.04). The results were similar when analyses were limited to 3MS scores collected before any on-study CVD events and in the cohort of women with no CVD history at baseline (data not shown). During follow-up, 108 cases of probable dementia (54 Alzheimer s disease, 10 vascular, 17 mixed, and 27 other) were encountered. A total of 316 women were classified as cognitively impaired (probable dementia or MCI). Figure 1 presents the cumulative incidence over time of the 316 cases of cognitive impairment according to baseline BP control and antihypertensive medication use. Women whose BP was controlled without antihypertensive medication were least likely to develop dementia or MCI. In contrast, women with uncontrolled BP despite use of antihypertensive medications were the most likely to develop these conditions (P 5.003). The cumulative incidence rates depicted in Figure 1 have not been adjusted for potential confounders. Table 4 presents results from proportional hazards regression models to describe associations between baseline hypertension status and BP control and probable dementia alone or combined with MCI. No differences were observed in the hazard of probable dementia in women with hypertension and women without hypertension (P 5.30). The

4 1452 JOHNSON ET AL. AUGUST 2008 VOL. 56, NO. 8 JAGS Table 1. Characteristics of the 7,149 Women from the Women s Health Initiative Memory Study at Baseline Variable Population Characteristic (% of Reported) Modified Mini-Mental State Examination Score Mean Standard Deviation With Hypertension, % Age at enrollment Ethnicity American Indian or Alaskan Native Asian Black Hispanic or Latino White Other Education ohigh school High school or General Educational Development diploma High school and o4 years of college years of college Body mass index, kg/m 2 o P-value.01 o.001 Physical activity (metabolic equivalents) per week Least activity (3.5) Moderate activity ( ) Greatest activity (412.5) P-value.008 o.001 Treatment of hypercholesterolemia (or statin use) No Yes Diabetes mellitus No Yes Smoking status Never Former Current P-value Depressive symptoms No Yes P-value o Alcoholic drinks per week (Continued )

5 JAGS AUGUST 2008 VOL. 56, NO. 8 WOMEN S HEALTH, HYPERTENSION AND COGNITIVE FUNCTION 1453 Table 1. (Contd.) Variable Population Characteristic (% of Reported) Modified Mini-Mental State Examination Score Mean Standard Deviation With Hypertension, % Postmenopausal hormone therapy Ever Never P-value Regular use of aspirin No Yes P-value.003 o.001 History of cardiovascular disease No Stroke Other Women s Health Initiative Hormone Trial treatment assignment Estrogen alone Estrogen alone placebo Estrogen1progestin Estrogen1progestin placebo P-value.49 w.03 w Hypertension defined as current drug therapy, systolic blood pressure 140 mmhg, or diastolic blood pressure 90 mmhg. w Controlling for differences between trials. hazard of any cognitive impairment (probable dementia and MCI) was greater (1.35, 95% CI , P 5.01) in women with hypertension than in women without hypertension in analyses adjusting for only baseline 3MS and WHI HT assignment. This difference was also attenuated with further adjustment for potential confounders and became nonsignificant (P 5.06). The factors contributing most strongly to this attenuation were age and ethnicity. No associations were found between baseline hypertension status stratified according to treatment and BP control and the incidence of probable dementia alone or combined with MCI. DISCUSSION In this group of cognitively intact healthy women aged 65 and older in the WHIMS, the presence of hypertension at baseline was not significantly associated with lower cognitive function as measured according to 3MS scores at baseline or during follow-up after adjustment for potential confounders. During follow-up, women who were not taking antihypertensive therapy and who had lower DBP (o60 mmhg) had slightly lower 3MS scores. Type of antihypertensive medication used did not appear to be associated with change in cognitive function over time. Furthermore, neither hypertension nor BP control was associated with incident probable dementia or MCI after adjustment for potential confounders. These WHIMS results demonstrate the importance of measuring and controlling for potential confounders during statistical modeling but should not be viewed as discouraging appropriate medical treatment for hypertension. The extensive published literature regarding the relationship between BP and cognitive function is challenging to interpret. Many of the previous studies have small sample sizes, are cross-sectional rather than prospective, and have high attrition (lost to follow-up) rates. Some studies do not account for important potential confounders such as age, sex, educational attainment, race or ethnicity, or level of BP control. Some studies do not have measured BPs and instead use a diagnosis of hypertension or antihypertensive treatment as the predictor variable. The outcome measures are varied as well, ranging from clinical diagnoses of dementia to sophisticated measures of cognitive function. The results of the current study are similar to those of others that have found no association between high BP or isolated systolic hypertension and various measures of cognitive decline. 23,42,43 For example, the East Boston Established Population for Epidemiologic Studies of the Elderly found no association between high BP measured either 4 or 13 years previously and Alzheimer s disease. 43 However, the results of the current study do not support other cross-sectional and longitudinal studies that have found that higher DPB and SBP and hypertension are associated with poorer cognitive outcomes. 13,44 49 For example, in the Framingham Study, untreated BP was found to be inversely related to cognitive impairment on a battery of tests measuring memory and attention. Furthermore, the results of the current study do not support the recent findings from the Cache County Study suggesting that antihypertensive medication

6 1454 JOHNSON ET AL. AUGUST 2008 VOL. 56, NO. 8 JAGS Table 2. Mean Baseline Modified Mini-Mental State Examination Score for Participants, Grouped According to Baseline Hypertension Status and Blood Pressure Unadjusted Demographic Covariate Adjusted w Full Covariate-Adjusted z Hypertension Status N (%) Mean Standard Error Hypertension No 3,593 (50.3) Yes 3,556 (49.7) P-value o Current treatment and BP control No current treatment and BPo140/90 3,593 (50.3) No current treatment and BP 140/90 1,333 (18.6) Current drug treatment and BP o140/90 1,150 (16.1) Current drug treatment and BP 140/90 1,073 (15.0) P-value o Systolic BP, mmhg o (1.3) ,561 (21.8) ,175 (44.4) ,774 (24.8) (7.6) P-value o Diastolic BP, mmhg o (4.0) ,523 (63.3) ,857 (29.5) (6.8) P-value Pulse pressure, mmhg o45 1,558 (21.8) ,146 (16.0) ,539 (21.5) ,471 (20.6) ,435 (20.1) P-value o Class of drug used in participants treated for high blood pressure Angiotensin-converting enzyme inhibitors 301 (14.0) Beta-blockers 178 (8.3) Calcium channel blockers 340 (15.8) Diuretics 319 (14.8) Other monotherapy 56 (2.6) Combination 958 (44.5) P-value Analyses without covariate adjustment. w Analyses with demographic covariate adjustment: age group, ethnicity, and education. z Analyses with full covariate adjustment: demographic covariates, body mass index, activity, treatment for hypercholesterolemia, diabetes mellitus, smoking status, depressive symptoms, alcohol intake, prior hormone therapy, regular use of aspirin, history of cardiovascular disease, and Women s Health Initiative Hormone Trial treatment assignment. Drug class missing for 71 women; analysis limited to women reporting current treatment for hypertension. BP 5 blood pressure. use is associated with lower incidence of dementia, 50 although it is difficult to interpret these findings given that 28% of the original Cache County Cohort was lost to follow-up and thus excluded from the analyses. There may be several reasons for the discrepant results between the current study and others reported in the literature regarding the relationship between cognitive function, BP, and antihypertensive therapy. There may be differential effects of mid-life and late-life hypertension on cognitive decline, with BP measured in middle age being more predictive of cognitive impairment and dementia than BP measured in old age. 16,17,43,51 54 It is also possible that the 3MS

7 JAGS AUGUST 2008 VOL. 56, NO. 8 WOMEN S HEALTH, HYPERTENSION AND COGNITIVE FUNCTION 1455 Table 3. Mean (Covariate Adjusted) Modified Mini- Mental State Examination (3MS) Scores During Follow- Up According to Baseline Hypertension Status and Blood Pressure Control Hypertension Status Minimally Demographic Covariate Adjusted Model Adjusted Model w Mean 3MS Score Standard Error Hypertension No Yes P-value o Baseline treatment and BP control No current treatment and BPo 140/90 No current treatment and BP 140/90 Current drug treatment and BP o140/90 Current drug treatment and BP 140/90 P-value o Class of drug used in participants treated for high blood pressure Angiotensin-converting enzyme inhibitors Beta-blockers Calcium channel blockers Diuretics Combination Other P-value Systolic BP, mmhg, without current drug treatment o P-value Systolic BP, mmhg, with current drug treatment o P-value Diastolic BP, mmhg, without current drug treatment o Diastolic BP, mmhg, with current drug treatment o P-value Pulse pressure, mmhg, without current drug treatment o (Continued ) Table 3. (Contd.) Hypertension Status Minimally Demographic Covariate Adjusted Model Adjusted Model w Mean 3MS Score Standard Error P-value Pulse pressure, mmhg, with current drug treatment o P-value o Adjusted for time since randomization, Women s Health Initiative Hormone Trial (WHI HT) treatment assignment, and baseline 3MS score. w Adjusted for time since randomization, WHI HT treatment assignment, baseline 3MS score, age group, ethnicity, and education. BP 5 blood pressure. and other similar screening instruments are not sensitive enough to detect subtle cognitive impairment during a short follow-up period in a healthy cognitively intact cohort. Some studies that used more-refined neuropsychological assessments have shown associations between hypertension and cognitive decline. 17,51,52,55 Although studies of the direct relationship between BP, hypertension, antihypertensive therapy, and cognition are Figure 1. Incidence of combined probable dementia (PD) and mild cognitive impairment (MCI) according to baseline hypertension status: Kaplan-Meier plot and results of a log-rank test (no covariate adjustments). Y-axis is not drawn to scale. At baseline, hypertension was defined as a self-report of current drug therapy for hypertension or clinic measurement of systolic blood pressure (BP) of 140 mmhg or greater, or diastolic BP of 90 mmhg or greater at enrollment. Within the category of hypertensive women, three categories defined according to current drug treatment (Trt) and BP control were further created: women with no current treatment and clinic BP 140/90 mmhg, women with current drug treatment and clinic BPo140/ 90 mmhg (controlled BP), and women with current drug treatment and clinic SBP 140/90 mmhg (uncontrolled BP).

8 1456 JOHNSON ET AL. AUGUST 2008 VOL. 56, NO. 8 JAGS Table 4. Relative Hazard of Probable Dementia and Composite Probable Dementia or Mild Cognitive Impairment (MCI) According to Baseline Hypertension Status Probable Dementia Composite Probable Dementia or MCI Baseline Hypertension and BP Level Minimally Adjusted Model Demographic Covariate Adjusted Model w Minimally Adjusted Model Hazard Ratio (95% Confidence Interval) Demographic Covariate Adjusted Model w Hypertension No Yes 1.22 ( ) 1.19 ( ) 1.35 ( ) 1.25 ( ) P-value Baseline treatment and BP control No treatment and BPo140/90 No treatment and 1.35 ( ) 1.34 ( ) 1.22 ( ) 1.17 ( ) BP 140/90 Drug treatment and 1.02 ( ) 0.95 ( ) 1.38 ( ) 1.27 ( ) BPo140/90 Drug treatment and 1.30 ( ) 1.28 ( ) 1.43 ( ) 1.30 ( ) BP 140/90 P-value Adjusted for Women s Health Initiative Hormone Trial (WHI HT) treatment assignment and baseline Modified Mini-Mental State Examination (3MS) score. w Adjusted for WHI HT treatment assignment, baseline 3MS score, age group, ethnicity, and education. BP 5 blood pressure. mixed, it has been postulated that hypertension plays an indirect role in cognitive impairment through the greater risk of cerebrovascular disease and stroke related to hypertension. In support of this hypothesis, evidence from the prospective Rotterdam Scan Study has demonstrated that elderly persons with silent brain infarcts at baseline detected according to magnetic resonance imaging scan have a greater risk of developing dementia and a steeper decline in cognitive function than persons without such lesions. 56 Given that hypertension is a known risk factor for stroke, these results provide evidence of a potential mechanism for the association between hypertension and cognitive function, even though it was not possible to demonstrate this relationship in WHIMS. This study has some notable strengths, including a large sample size, high rates of retention, and thorough collection of data, including measurement of BP. These results from WHIMS expand the existing literature by examining these relationships in a group of healthy, older, ethnically diverse, postmenopausal women, a group that has been relatively understudied. Furthermore, the rich data sets from WHI and WHIMS allow for adjustment of potential confounders that were not always available in other data sets and are important in understanding the relationship between BP and cognition. This study also has several limitations. Women in WHIMS may not be representative of the U.S. population in this age group. Whereas the National Center for Health Statistics estimates that 73% to 84% of the women in the age range of the WHIMS participants have hypertension, only 50% of the participants had this condition. 2 Although the WHIMS participants appeared to be less likely to have had hypertension, it is unknown whether this difference in the prevalence of hypertension may affect the relationship between BP and cognitive function. These analyses may also underestimate the relationship between hypertension and cognition, because women who had extremely high BP (4200/105 mmhg) or a recent history of stroke (within previous 6 months) were excluded from participation in WHI HT. In addition, the sample was predominantly Caucasian (86.9%) and the sample size in minority groups was much smaller. Given that race is associated with 3MS score, it is possible that the association between BP and cognition was underestimated even after attempting to adjust for race in the analyses. Furthermore, the healthy participants in WHIMS had low rates of cognitive decline and dementia, which may limit the power to detect associations between hypertension and cognition. Moreover, an average of 4.5 years of follow-up may not be long enough to detect associations between hypertension and cognitive decline in a group of healthy cognitively intact participants. Further follow-up of the WHIMS participants is ongoing. CONCLUSION Hypertension and high BP were not associated with MCI or probable dementia over time in older, healthy, cognitively intact, postmenopausal women enrolled in WHIMS after other potential confounders were taken into account. These analyses should not be viewed as discouraging appropriate medical treatment for hypertension. ACKNOWLEDGMENTS The WHIMS was funded by Wyeth Pharmaceuticals, Inc, St. Davids, PA. The WHI is funded by the National Heart,

9 JAGS AUGUST 2008 VOL. 56, NO. 8 WOMEN S HEALTH, HYPERTENSION AND COGNITIVE FUNCTION 1457 Lung, and Blood Institute of the National Institutes of Health, U.S. Department of Health and Human Services. Conflict of Interest: Karen C. Johnson: research contracts with Bionova, Pfizer, Novartis, and Merck. Karen L. Margolis: advisory board for King Pharmaceuticals and Bristol-Myers Squibb. Mark A. Espeland: consultant funding from Sankyo Pharmaceuticals and Schering Plough; Data and Safety Monitoring Board for Wyeth Pharmaceuticals. Kamal H. Masaki: speakers bureau for Pfizer. Author Contributions: All authors were involved in the acquisition of subjects and data, analysis and interpretation of the data, and preparation of the manuscript. Sponsor s Role: Wyeth-Ayerst Pharmaceuticals provided funding for the WHIMS and the blinded study medication for the WHI HT but was not involved in the design, methods, subject recruitment, data collections, analysis, or preparation of this manuscript. 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Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 2003;348: Appendix The following persons are the principal investigators in WHIMS. Clinical Centers: Albert Einstein College of Medicine, Bronx, NY: Sylvia Wassertheil-Smoller; Baylor College of Medicine, Houston, TX: Jennifer Hays; Brigham and Women s Hospital, Harvard Medical School, Boston, MA: JoAnn Manson; Brown University, Providence, RI: AnnLouise R. Assaf; Emory University, Atlanta, GA: Lawrence Phillips; George Washington University Medical Center, Washington, DC: Judith Hsai; Harbor-UCLA Research and Education Institute, Torrance, CA: Rowan Chebowski; Kaiser Permanente Division of Research, Oakland, CA: Bette Caan; Medical College of Wisconsin, Milwaukee, WI: Jane Morley Kotchen; Medlantic Research Institute, Washington, DC: Maureen Passaro; Northwestern University, Chicago, IL: Linda Van Horn; Cook County Hospital, Rush-Presbyterian St. Luke s Medical Center, Chicago, IL: Lynda Powell; Stanford Center for Research in Disease Prevention, Stanford University, Stanford, CA: Marcia L. Stefanick; State University of New York at Stony Brook, Stony Brook, NY: Dorothy Lane; The Ohio State University, Columbus, OH: Rebecca Jackson; University of Alabama at Birmingham, Birmingham, AL: Beth Lewis; University of Arizona, Tucson/Phoenix, AZ: Tamsen Bassford; University of Buffalo, Buffalo, NY: Maurizio Trevisan; University of California at Davis, Sacramento, CA: John Robbins; University of California at Irvine, Orange, ca: Allan Hubbell; University of California at Los Angeles, Los Angeles, CA: Howard Judd; University of California at San Diego, LaJolla/Chula Vista, CA: Robert D. Langer; University of Cincinnati, Cincinnati, OH: Margery Gass; University of Florida, Gainesville/Jacksonville, FL: Marian Limacher; University of Hawaii, Honolulu, HI: David Curb; University of Iowa, Iowa City/ Davenport, IA: Robert Wallace; University of Massachusetts, Worcester, MA: Judith Ockene; University of Medicine and Dentistry of New Jersey, Newark, NJ: Norman Lasser; University of Minnesota, Minneapolis, MN: Karen Margolis; University of Nevada, Reno, NV: Robert Brunner; University of North Carolina, Chapel Hill, NC: Carol Murphy; University of Tennessee at Memphis, Memphis, TN: Karen C. Johnson; University of Texas Health Science Center, San Antonio, TX: Donald Royall; University of Wisconsin, Madison, WI: Catherine Allen; Wake Forest University School of Medicine, Winston-Salem, NC: Mara Vitolins; and Wayne State University School of Medicine/Hutzel Hospital, Detroit, MI: Susan Hendrix. Coordinating Centers: WHIMS Coordinating Center: Wake Forest University School of Medicine, Winston-Salem, NC: Sally Shumaker; Fred Hutchinson Cancer Research Center, Seattle, WA: Deborah Bowen. The following persons are the principal investigators in the WHI. Program Office: National Heart, Lung, and Blood Institute, Bethesda, Maryland Barbara Alving, Jacques Rossouw, Linda Pottern. Clinical Coordinating Center: Fred Hutchinson Cancer Research Center, Seattle, WA. Ross Prentice, Garnet Anderson, Andrea LaCroix, Ruth E. Patterson, Anne McTiernan; (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker, Pentti Rautaharju; (Medical Research Labs, Highland Heights, KY) Evan Stein; (University of California at San Francisco, San Francisco, CA) Steven Cummings; (University of Minnesota, Minneapolis, MN) John Himes; (University of Washington, Seattle, WA) Bruce Psaty. Clinical Centers: (Albert Einstein College of Medicine, Bronx, NY) Sylvia Wassertheil-Smoller; (Baylor College of Medicine, Houston, TX) Jennifer Hays; (Brigham and Women s Hospital, Harvard Medical School, Boston, MA) JoAnn Manson; (Brown University, Providence, RI) Annlouise R. Assaf; (Emory University, Atlanta, GA) Lawrence Phillips; (Fred Hutchinson Cancer Research Center, Seattle, WA) Shirley Beresford; (George Washington University Medical Center, Washington, DC) Judith Hsia; (Harbor-UCLA Research and Education Institute, Torrance, CA) Rowan Chlebowski; (Kaiser Permanente Center for Health Research, Portland, OR) Cheryl Ritenbaugh; (Kaiser Permanente Division of Research, Oakland, CA) Bette Caan; (Medical College of Wisconsin, Milwaukee, WI) Jane Morley Kotchen; (MedStar Research Institute/Howard University, Washington, DC) Barbara V. Howard; (Northwestern University, Chicago/ Evanston, IL) Linda Van Horn; (Rush-Presbyterian St. Luke s Medical Center, Chicago, IL) Henry Black; (Stanford Center for Research in Disease Prevention, Stanford University, Stanford, CA) Marcia L. Stefanick; (State University of New York at Stony Brook, Stony Brook, NY) Dorothy Lane; (The Ohio State University, Columbus, OH) Rebecca Jackson; (University of Alabama at Birmingham, Birmingham, AL) Cora Beth Lewis; (University of Arizona, Tucson/Phoenix, AZ) Tamsen Bassford; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende; (University of California at Davis, Sacramento, CA) John Robbins; (University of California at Irvine, Orange, CA) Allan Hubbell; (University of California at Los Angeles, Los Angeles, CA) Howard Judd; (University of California at San Diego, LaJolla/Chula Vista, CA) Robert D. Langer; (University of Cincinnati, Cincinnati, OH) Margery Gass; (University of Florida, Gainesville/Jacksonville, FL) Marian Limacher; (University of Hawaii, Honolulu, HI) David Curb; (University of Iowa, Iowa City/Davenport, IA) Robert Wallace; (University of Massachusetts/Fallon Clinic, Worcester, MA) Judith Ockene; (University of Medicine and Dentistry of New Jersey, Newark, NJ) Norman Lasser; (University of Miami, Miami, FL) Mary Jo O Sullivan; (University of Minnesota, Minneapolis, MN) Karen Margolis; (University of Nevada, Reno, NV) Robert Brunner; (University of North Carolina, Chapel Hill, NC) Gerardo Heiss; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller; (University of Tennessee, Memphis, TN) Karen C. Johnson; (University of Texas Health Science Center, San Antonio, TX) Robert Brzyski; (University of Wisconsin, Madison, WI) Gloria Sarto; (Wake Forest University School of Medicine, Winston-Salem, NC) Denise Bonds; (Wayne State University School of Medicine/Hutzel Hospital, Detroit, MI) Susan Hendrix. Former WHI Investigators: Catherine Allen (University of Wisconsin, Madison, WI), Gregory Burke (Wake Forest University School of Medicine, Winston- Salem, NC), Sandy Dougherty (University of Nevada, Reno, NV), Richard Carleton (Brown University, Providence, RI). Deceased.