Abstract
BACKGROUND
To investigate the relationships of hypertension, antihypertensive treatment, and sodium intake on cognitive decline in older women.
METHODS
Prospective follow-up of 6,426 cognitively intact women aged 65–79 years enrolled in the Women’s Health Initiative Memory Study (WHIMS) with a median follow-up of 9.1 years. Dietary sodium intake was determined by food frequency questionnaires. Hypertension was defined as self-report of current drug therapy for hypertension. Blood pressure (BP) control was assessed by treatment for hypertension and clinic measurement of systolic BP ≥ 140mm Hg or diastolic BP ≥ 90mm Hg at baseline. Cognitive functioning was assessed annually by global cognitive screening, neurocognitive, and neuropsychiatric evaluations. Cognitive decline was identified by the incidence of mild cognitive impairment (MCI) or probable dementia (PD). Cox proportional hazards analyses were used to calculate hazard ratios (HRs).
RESULTS
Hypertension was associated with an increased risk for cognitive decline (HR 1.20; 95% confidence interval (CI) 1.04, 1.39; P = 0.02). Among women with antihypertensive medication, those with BP ≥140/90mm Hg (uncontrolled BP) were at highest risk for developing cognitive decline (HR 1.30; 95% CI 1.05, 1.60) compared to women without treatment and BP <140/90mm Hg (controlled BP). Sodium intake >1,500mg/day did not alter the risk for cognitive decline in hypertensive women or women with antihypertensive treatment (P for interaction = 0.96 or 0.97).
CONCLUSIONS
Women with antihypertensive treatment and uncontrolled BP showed highest risk estimates for developing cognitive decline compared to non-hypertensive women. Sodium intake did not modify the risk for cognitive decline in women with hypertension or receiving antihypertensive medication.
CLINICAL TRIAL REGISTRATION
http://www.clinicaltrials.gov. Unique identifier: NCT00685009 and NCT00745056
Keywords: antihypertensive treatment, blood pressure, cognitive decline, dietary sodium, hypertension.
The number of individuals affected by cognitive decline is expected to rise over the next few decades.1 Investigating the effects of risk factors and life-style modification on the preservation of cognitive functioning is of major public health interest.2 Blood pressure (BP) control has emerged to be a key target for long-term interventions to reduce cognitive deterioration but age-dependent results exist.2,3 Hypertension in mid-life is associated with cognitive decline while antihypertensive treatment is shown to be protective.4,5 Nonetheless, in elderly individuals data on the effect of BP control on cognitive decline are still inconsistent.3,6 Differences may be explained by the duration of exposure before incident disease.6 Late-life onset hypertension simply may not last long enough to result in cognitive dysfunction. Large population-based long-term studies are needed for further clarification.
Dietary sodium intake is related to the incidence and severity of hypertension.7–9 In 2010, mean sodium intake in the United States and Canada was approximately 3,800mg/day,10 even though the physiologically necessary daily intake of sodium is estimated to be only approximately 180 to 230mg/day.11 But, while scientific evidence for the benefits of dietary sodium reduction on BP control is strong,7,12,13 to this point surprisingly little is known about the effect of sodium intake on hypertension and cognitive decline.14
The objective of this study was first to evaluate the effect of hypertension and antihypertensive treatment on cognitive decline in elderly postmenopausal women. Second, we aimed to investigate the effect of dietary sodium on the incidence of cognitive decline in women with hypertension or antihypertensive medication.
METHODS
Study population
The total study population included 7,479 postmenopausal women enrolled in the Women’s Health Initiative Memory Study (WHIMS). WHIMS consisted of two parallel randomized clinical trials designed to investigate the effect of estrogen alone (E alone) or in combination with progestin (E + P) on the incidence of probable dementia (PD) and mild cognitive impairment (MCI).15–18 WHIMS participants were recruited between May 1996 and December 1999 at 39 US clinical centers from women enrolled in the Women’s Health Initiative (WHI) hormone therapy trials who were aged 65–79 years and were free of dementia at enrollment. Details of the study population and of the initial screening process for the WHI and WHIMS have been reported previously.18,19 WHIMS participants returned to in-clinic visits annually for cognitive assessment and were contacted by semiannual questionnaires to ascertain selected exposures and medical outcomes.18,19 The WHIMS E + P trial ended earlier than planned in July 200216,17 due to adverse risk to benefit ratio in the WHI parent study20; and in February 2004, the E Alone Study ended with early termination of WHI trial.15,21,22 WHIMS participants continued annual post-trial cognitive assessment through the WHIMS Extension Study until 2007/2008 and then through the “Women’s Health Initiative (WHI) Memory Study-Epidemiology of Cognitive Health Outcomes” (WHIMS-ECHO) study to present.
For this analysis, we excluded WHIMS participants with missing baseline or follow-up information (n = 307). Eight women with MCI at baseline and 532 women with missing covariate data were not considered; 206 participants with incomplete dietary information or with extreme calorie intake (i.e., <500 kcal or > 3,500 kcal per day) were excluded from further analysis.23 Our final study population was 6,426 postmenopausal women (Figure 1). Individuals were followed up through 31 December 2012 with a median follow-up of 9.11 years.
Figure 1.
Study inclusion.
Exposure assessment
Sodium intake was derived from self-report Women’s Health Initiative food frequency questionnaires (WHI-FFQs) that were administered to all WHI participants at baseline.19,24,25 The WHI-FFQ was based on the Block FFQ and has demonstrated good validity.19,25,26 Nonetheless, as several limitations of dietary sodium assessment by FFQs have been reported previously,27 we additionally conducted separate analyses based on 24-hour urine excretions in a subsample of women to correct dietary self-report data of sodium intake for potential measurement errors (Supplementary Tables 1 and 2).28
BP was measured by certified staff using standardized procedures in a WHI clinic.19 The average of two baseline readings taken at the same clinic visit was used for the analyses. Hypertension was defined as self-report of current drug therapy for hypertension. BP control was assessed by treatment for hypertension and clinic measurement of systolic BP ≥ 140mm Hg or diastolic BP ≥ 90mm Hg at baseline. Antihypertensive medication data were collected during in-person clinic visits at baseline.29
Outcome assessment
The primary outcome measure for this study was cognitive decline (MCI/PD) which we identified by the incidence of “MCI or PD.” Cognitive functioning was evaluated in all women enrolled in WHIMS annually using the Modified Mini-Mental State Examination (3MS) as an initial screening test. It summed from 0 to 100 with higher scores reflecting better cognitive functioning.30 If a participant scored below preestablished cut-points depending on previous education, further neurocognitive and neuropsychiatric examinations were conducted to establish the presence of MCI or PD. The diagnosis MCI or PD was based on the criteria established by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.31 A detailed description of the WHIMS protocol has been published previously.17,18
MCI was diagnosed if the participant showed poor performance (10th or lower percentile) in at least 1 area of cognitive function on modified neuropsychological tests established by the Consortium to Establish a Registry for Alzheimer’s Disease32 or if the participant was reported to suffer from some functional impairment excluding a basic activity of daily living by a reliable informant. Prior to the diagnosis, other medical or psychiatric conditions, including depression were excluded as potential reasons for the participant’s cognitive functioning. Participants showing additional impairments in social and occupational functioning secondary to cognitive impairment and not otherwise explained by other medical causes were classified as having PD. All clinical and test data including MCI and PD cases were transmitted to the WHIMS Clinical Coordinating Center for review and central adjudication.15,17
In 2008, cognitive assessment in WHIMS transitioned from in-clinic post-trial annual follow-up to participation in the WHIMS-Epidemiology of Cognitive Health Outcomes’ (WHIMS-ECHO) study. Instead of in-clinic visits and face-to-face evaluation, participants in WHIMS-ECHO underwent an annual centralized, validated cognitive telephone interview for tracking changes in cognitive status as previously described.
Covariates
Information on all covariates was derived from self-report or by physical measure at WHI baseline.19 Cardiovascular disease was defined as history of myocardial infarction, angina pectoris, atrial fibrillation, heart failure, peripheral vascular disease, coronary bypass surgery, angioplasty, carotid endarterectomy, or stroke. Women were coded positive for diabetes on the basis of self-report of diabetes or diabetes treatment. Body mass index was defined as weight in kg/height in m2. Physical activity was measured with metabolic equivalent tasks (METs) in hours per week.33
Statistical analysis
The characteristics of included women are presented by hypertension status at baseline (Table 1).
Table 1.
Baseline characteristics by hypertension status
| Normotensive | Hypertensive | P value | ||||
|---|---|---|---|---|---|---|
| N | % | N | % | |||
| Age group (year) | 65–69 | 1,662 | 50.79 | 1,340 | 42.49 | <0.0001 |
| 70–74 | 1,126 | 34.41 | 1,167 | 37.00 | . | |
| 75–79 | 484 | 14.79 | 647 | 20.51 | ||
| Race: Caucasian | No | 295 | 9.02 | 472 | 14.97 | <0.0001 |
| Yes | 2,977 | 90.98 | 2,682 | 85.06 | . | |
| Education | <HS diploma/GED | 200 | 6.11 | 234 | 7.42 | 0.0121 |
| HS diploma/GED | 693 | 21.18 | 728 | 23.09 | . | |
| >HS diploma/GED | 2,379 | 72.71 | 2,192 | 69.52 | . | |
| Smoking status | Never | 1,729 | 52.84 | 1,710 | 54.23 | 0.1378 |
| Past | 1,305 | 39.88 | 1,251 | 39.68 | . | |
| Current | 238 | 7.27 | 192 | 6.09 | . | |
| Alcohol use | Nondrinker | 930 | 28.42 | 1,139 | 36.12 | <0.0001 |
| ≤1 drink/day | 1,079 | 32.98 | 990 | 31.40 | . | |
| >1 drink/day | 1,263 | 38.60 | 1,025 | 32.50 | . | |
| Body mass index (kg/m2) | <25 | 1,154 | 35.27 | 731 | 23.18 | <0.0001 |
| 25 – <30 | 1,204 | 36.80 | 1,146 | 36.35 | . | |
| ≥30 | 914 | 27.93 | 1,276 | 40.47 | . | |
| Physical activity, METs/week | 0–1.5 | 672 | 20.54 | 759 | 24.07 | 0.0001 |
| 1.5–8 METs | 989 | 30.23 | 996 | 31.59 | . | |
| 8–19 METs | 908 | 27.75 | 831 | 26.35 | . | |
| ≥19 METs | 703 | 21.49 | 568 | 18.01 | . | |
| Depressive symptoms | No | 3,229 | 98.69 | 3,120 | 98.92 | 0.3851 |
| Yes | 43 | 1.31 | 34 | 1.08 | . | |
| Antihypertensive medication | No | 2,979 | 91.05 | 1,205 | 38.21 | <0.0001 |
| Yes | 293 | 8.95 | 1,949 | 61.79 | . | |
| Diabetes | No | 3,150 | 96.27 | 2,877 | 91.22 | <0.0001 |
| Yes | 122 | 3.73 | 277 | 8.78 | . | |
| History of cardiovascular disease | No | 2,939 | 89.82 | 2,575 | 81.64 | <0.0001 |
| Yes | 333 | 10.18 | 579 | 18.36 | . | |
| WHI menopausal hormone therapy (HT) | Placebo | 1,677 | 51.25 | 1,569 | 49.75 | 0.2321 |
| Treatment | 1,595 | 48.75 | 1,585 | 50.25 | . | |
Abbreviation: HS, high school; WHI, Women’s Health Initiative.
To analyze the effect of hypertension or antihypertensive treatment on cognitive decline incidence rates of MCI or PD were determined (Tables 2–7). Corresponding rate ratios were calculated by dividing the rate among women with hypertension or antihypertensive treatment by the rate without hypertension or antihypertensive medication. Three Cox proportional hazards models were used to estimate the risk for developing cognitive decline. To control for confounding, we first adjusted our analyses for menopausal hormone therapy (WHI HT arm—active vs. placebo), age (10-year age group), race, education level, and baseline 3MSE level (Model 1). Additionally, we adjusted for alcohol, smoking status, physical activity, diabetes status, categorical body mass index, depression, and total energy intake (Model 2). Last, we added history of cardiovascular disease to our model (Model 3).
Table 2.
Blood pressure control and mild cognitive impairment
| Mild cognitive impairment | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Model 1 | P value | Model 2 | P value | Model 3 | P value | ||||||||||
| N | Cases | Hazard ratio | Lower CL | Upper CL | Sum | Hazard ratio | Lower CL | Upper CL | Sum | Hazard ratio | Lower CL | Upper CL | Sum | ||
| Hypertension | No | 3,272 | 215 | 1.00 | . | . | 0.006 | 1.00 | . | . | 0.008 | 1.00 | . | . | 0.03 |
| Yes | 3,154 | 283 | 1.29 | 1.08 | 1.55 | . | 1.28 | 1.07 | 1.54 | . | 1.23 | 1.02 | 1.48 | ||
| Treatment with antihypertensive medication and blood pressure | No treatment and BP <140/90 (untreated, controlled) | 2,979 | 186 | 1.00 | . | . | 0.003 | 1.00 | . | . | 0.007 | 1.00 | . | . | 0.11 |
| No treatment and BP ≥140/90 (untreated, uncontrolled) | 1,068 | 85 | 1.10 | 0.85 | 1.42 | . | 1.10 | 0.85 | 1.43 | . | 1.09 | 0.84 | 1.41 | . | |
| Treatment and BP < 140/90 (treated, controlled) | 1,323 | 127 | 1.44 | 1.15 | 1.81 | . | 1.44 | 1.14, | 1.81 | . | 1.31 | 1.03, | 1.66 | . | |
| Treatment and BP ≥ 140/90 (treated, uncontrolled) | 1,056 | 100 | 1.44 | 1.13 | 1.85 | . | 1.40 | 1.09 | 1.81 | . | 1.27 | 0.98, | 1.65 | . | |
Model 1 adjusted for age, race, education, baseline 3MSE, and WHI menopausal hormone therapy arm.
Model 2 adjusted for age, race, education, WHI menopausal hormone therapy arm, baseline 3MSE, alcohol, smoking status, physical activity, diabetes status, BMI, depression, and total energy intake.
Model 3 adjusted for age, race, education, WHI menopausal hormone therapy arm, baseline 3MSE, alcohol, smoking status, physical activity, diabetes status, BMI, depression, total energy intake, and history of cardiovascular disease.
Abbreviations: BP, blood pressure; CL, confidence limit.
Table 3.
Blood pressure control and probable dementia
| Probable dementia | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Model 1 | P value | Model 2 | P value | Model 3 | P value | ||||||||||
| N | Cases | Hazard ratio | Lower CL | Upper CL | Sum | Hazard ratio | Lower CL | Upper CL | Sum | Hazard ratio | Lower CL | Upper CL | Sum | ||
| Hypertension | No | 3,272 | 188 | 1.00 | . | . | 0.30 | 1.00 | . | . | 0.27 | 1.00 | . | . | 0.32 |
| Yes | 3,154 | 201 | 1.11 | 0.91 | 1.36 | . | 1.12 | 0.92 | 1.38 | . | 1.11 | 0.90 | 1.37 | ||
| Treatment with antihypertensive medication and blood pressure | No treatment and BP <140/90 (untreated, controlled) | 2,979 | 168 | 1.00 | . | . | 0.36 | 1.00 | . | . | 0.32 | 1.00 | . | . | 0.48 |
| No treatment and BP ≥140/90 (untreated, uncontrolled) | 1,068 | 67 | 1.10 | 0.75 | 1.33 | . | 1.01 | 0.76 | 1.35 | . | 1.01 | 0.76 | 1.34 | . | |
| Treatment and BP <140/90 (treated, controlled) | 1,323 | 82 | 1.07 | 0.82 | 1.39 | . | 1.07 | 0.82 | 1.41 | . | 1.04 | 0.79 | 1.37 | . | |
| Treatment and BP ≥140/90 (treated, uncontrolled) | 1,056 | 72 | 1.28 | 0.97 | 1.70 | . | 1.30 | 0.98 | 1.73 | . | 1.25 | 0.93 | 1.67 | . | |
Model 1 adjusted for age, race, education, baseline 3MSE, and WHI menopausal hormone therapy arm.
Model 2 adjusted for age, race, education, WHI menopausal hormone therapy arm, baseline 3MSE, alcohol, smoking status, physical activity, diabetes status, BMI, depression, and total energy intake.
Model 3 adjusted for age, race, education, WHI menopausal hormone therapy arm, baseline 3MSE, alcohol, smoking status, physical activity, diabetes status, BMI, depression, total energy intake, and history of cardiovascular disease.
Abbreviation: BP, blood pressure; CL, confidence limit.
Table 6.
Blood pressure control and probable dementia
| Probable dementia | |||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Model 1 | Model 2 | Model 3 | |||||||||||||||
| N | Cases | Annualized % | Mean fup (year) | Hazard ratio | lower CL | upper CL | P value | Hazard ratio | lower CL | upper CL | P value | Hazard ratio | lower CL | upper CL | P value | ||
| Hypertension control | No treatment and BP <140/90 (untreated, controlled) | 2,979 | 168 | 0.56 | 10.06 | 1.00 | . | . | 0.63 | 1.00 | . | . | 0.76 | 1.00 | . | . | 0.85 |
| Treatment and BP < 140/90 (treated, controlled) | 1,323 | 82 | 0.66 | 9.33 | 1.07 | 0.82 | 1.40 | . | 1.05 | 0.79 | 1.38 | . | 0.97 | 0.73 | 1.30 | . | |
| Treatment with antihypertensive medication and blood pressure | Treatment and BP < 140/90 (treated, controlled) | 1,323 | 82 | 0.66 | 9.33 | 1.00 | . | . | . | 1.00 | . | . | . | 1.00 | . | . | 0.42 |
| No treatment and BP ≥140/90 (untreated, uncontrolled) | 1,068 | 67 | 0.66 | 9.58 | 0.93 | 0.67 | 1.29 | 0.35 | 0.92 | 0.66 | 1.28 | 0.36 | 0.94 | 0.67 | 1.32 | . | |
| Treatment and BP ≥ 140/90 (treated, uncontrolled) | 1,056 | 72 | 0.77 | 8.82 | 1.19 | 0.86 | 1.63 | . | 1.17 | 0.85 | 1.62 | . | 1.17 | 0.85 | 1.62 | . | |
Model 1 adjusted for age, race, education, baseline 3MSE, and WHI menopausal hormone therapy arm.
Model 2 adjusted for age, race, education, WHI menopausal hormone therapy arm, baseline 3MSE, alcohol, smoking status, physical activity, diabetes status, BMI, depression, and total energy intake.
Model 3 adjusted for age, race, education, WHI menopausal hormone therapy arm, baseline 3MSE, alcohol, smoking status, physical activity, diabetes status, BMI, depression, total energy intake, and history of cardiovascular disease.
Abbreviation: BP, blood pressure; CL, confidence limit.
Table 7.
Blood pressure control and cognitive decline
| Mild cognitive impairment or probable dementia | |||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Model 1 | Model 2 | Model 3 | |||||||||||||||
| N | Cases | Annualized % | Mean fup (year) | Hazard ratio | lower CL | upper CL | P value | Hazard ratio | lower CL | upper CL | P value | Hazard ratio | lower CL | upper CL | P value | ||
| Hypertension control | No treatment and BP <140/90 (untreated, controlled) | 2,979 | 303 | 1.02% | 9.93 | 1.00 | . | . | 0.01 | . | . | . | . | 1.00 | . | . | 0.19 |
| Treatment and BP <140/90 (treated, controlled) | 1,323 | 175 | 1.46% | 9.09 | 1.27 | 1.05 | 1.54 | . | 1.18 | 0.93 | 1.49 | . | 1.15 | 0.94 | 1.40 | . | |
| Treatment with antihypertensive medication and blood pressure | Treatment and BP <140/90 (treated, controlled) | 1,323 | 175 | 1.46% | 9.09 | 1.00 | . | . | . | 1.00 | . | . | . | 1.00 | . | . | 0.28 |
| No treatment and BP ≥140/90 (untreated, uncontrolled) | 1,068 | 128 | 1.28% | 9.39 | 0.85 | 0.67 | 1.07 | 0.12 | 0.85 | 0.67 | 1.07 | 0.16 | 0.88 | 0.70 | 1.12 | . | |
| Treatment and BP ≥140/90 (treated, uncontrolled) | 1,056 | 147 | 1.62% | 8.57 | 1.09 | 0.87 | 1.36 | . | 1.08 | 0.86 | 1.35 | . | 1.08 | 0.86 | 1.35 | . | |
Model 1 adjusted for age, race, education, baseline 3MSE, and WHI menopausal hormone therapy arm.
Model 2 adjusted for age, race, education, WHI menopausal hormone therapy arm, baseline 3MSE, alcohol, smoking status, physical activity, diabetes status, BMI, depression, and total energy intake.
Model 3 adjusted for age, race, education, WHI menopausal hormone therapy arm, baseline 3MSE, alcohol, smoking status, physical activity, diabetes status, BMI, depression, total energy intake, and history of cardiovascular disease.
Abbreviation: BP, blood pressure; CL, confidence limit.
To assess the effect of sodium intake on the relationship between hypertension, antihypertensive medication use, and cognitive decline, Cox proportional hazards regression models were performed separately according to various amounts of sodium intake. Data on sodium intake were derived from FFQs (Table 8 and 9) and corrected using calibration equations based on 24-hour urine excretions (Supplementary Tables 1 and 2).
Table 8.
Incidence and hazard ratios by sodium intake and hypertension
| Hypertension | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No | Yes | Base model | Multivariate model | ||||||||||
| N | Annualized % | N | Annualized % | Hazard ratio | Lower CL | Upper CL | P for interaction | Hazard ratio | lower CL | upper CL | P for interaction | ||
| MCI | ≤1,500mg/day | 51 | 0.08% | 36 | 0.12% | 1.20 | 0.78 | 1.85 | . | 1.09 | 0.70 | 1.68 | . |
| 1,501–2,999mg/day | 155 | 0.06% | 122 | 0.09% | 1.35 | 1.06 | 1.71 | 0.35 | 1.23 | 0.96 | 1.57 | 0.44 | |
| >3,000mg/day | 65 | 0.04% | 69 | 0.08% | 1.73 | 1.23 | 2.43 | . | 1.52 | 1.07 | 2.15 | . | |
| PD | ≤1,500mg/d | 32 | 0.05% | 26 | 0.08% | 1.60 | 0.95 | 2.70 | . | 1.57 | 0.92 | 2.66 | . |
| 1,501–2,999mg/day | 128 | 0.05% | 85 | 0.06% | 1.17 | 0.88 | 1.54 | 0.31 | 1.16 | 0.87 | 1.54 | 0.25 | |
| >3,000mg/day | 75 | 0.05% | 43 | 0.05% | 0.97 | 0.66 | 1.41 | . | 0.91 | 0.62 | 1.35 | . | |
| MCI/PD | ≤1,500mg/day | 51 | 0.08% | 36 | 0.12% | 1.30 | 0.91 | 1.87 | . | 1.23 | 0.85 | 1.78 | . |
| 1,501–2,999mg/day | 155 | 0.06% | 122 | 0.09% | 1.29 | 1.06 | 1.57 | 1.00 | 1.24 | 1.02 | 1.52 | 0.96 | |
| >3,000mg/day | 65 | 0.04% | 69 | 0.08% | 1.29 | 0.98, | 1.69 | . | 1.19 | 0.90 | 1.57 | . | |
Base model adjusted for age, race, education, baseline 3MSE, and WHI menopausal hormone therapy arm.
Multivariate model adjusted for age, race, education, WHI menopausal hormone therapy arm, baseline 3MSE, alcohol, smoking status, physical activity, diabetes status, BMI, depression, total energy intake, and history of cardiovascular disease.
Abbreviations: MCI, mild cognitive impairment; PD, probable dementia.
Table 9.
Incidence and hazard ratios by sodium intake and antihypertensive medication use
| Antihypertensive medication | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No | Yes | Base model | Multivariate model | ||||||||||
| N | Annualized % | N | Annualized % | Hazard ratio | Lower CL | Upper CL | P for interaction | Hazard ratio | Lower CL | Upper CL | P for interaction | ||
| MCI | ≤1,500mg/day | 55 | 0.08% | 32 | 0.11% | 1.12 | 0.72 | 1.74 | . | 1.01 | 0.64 | 1.57 | . |
| 1,501–2,999mg/day | 166 | 0.06% | 111 | 0.08% | 1.28 | 1.01 | 1.64 | 0.18 | 1.16 | 0.90 | 1.48 | 0.24 | |
| >3,000mg/day | 67 | 0.04% | 67 | 0.08% | 1.79 | 1.27 | 2.51 | . | 1.55 | 1.10 | 2.20 | . | |
| PD | ≤1,500mg/day | 34 | 0.05% | 24 | 0.08% | 1.58 | 0.93 | 2.68 | . | 1.55 | 0.91 | 2.65 | . |
| 1,501–2,999mg/day | 133 | 0.05% | 80 | 0.06% | 1.16 | 0.88 | 1.54 | 0.48 | 1.15 | 0.87 | 1.54 | 0.42 | |
| >3,000mg/day | 75 | 0.05% | 43 | 0.05% | 1.07 | 0.73 | 1.55 | . | 1.01 | 0.68 | 1.48 | . | |
| MCI/PD | ≤1,500mg/day | 55 | 0.08% | 32 | 0.11% | 1.25 | 0.86 | 1.80 | . | 1.18 | 0.81 | 1.71 | . |
| 1,501–2,999mg/day | 166 | 0.06% | 111 | 0.08% | 1.25 | 1.02 | 1.52 | 0.88 | 1.19 | 0.97 | 1.46 | 0.97 | |
| >3,000mg/day | 67 | 0.04% | 67 | 0.08% | 1.36 | 1.03 | 1.78 | . | 1.24 | 0.94 | 1.64 | . | |
Base model adjusted for age, race, education, baseline 3MSE and WHI menopausal hormone therapy arm.
Multivariate model adjusted for age, race, education, WHI menopausal hormone therapy arm, baseline 3MSE, alcohol, smoking status, physical activity, diabetes status, BMI, depression, total energy intake, and history of cardiovascular disease.
Abbreviations: MCI, mild cognitive impairment; PD, probable dementia.
All P values were 2-tailed. All the analyses were conducted using SAS statistical software (version 9.3; SAS Institute, Cary, NC).
RESULTS
The characteristics of women by hypertension status are shown in Table 1. Hypertensive women were older, had higher body mass index, lower education, were less physically active and more likely to be treated for diabetes compared to normotensive women. Women with hypertension also had slightly lower 3MS scores and consumed on average more sodium per day.
During a median follow-up of 9.1 years 498 women were diagnosed with “MCI,” 389 with “PD” and 753 women with “MCI or PD” (MCI/PD). Three hundred and sixty-four women developed MCI only, 134 women with MCI further developed PD and 255 women were diagnosed with PD without having had a previous diagnosis of MCI. The multivariate-adjusted hazard ratios (HRs) for incident MCI, PD, or MCI/PD related to BP control are presented in Tables 2–7. After fully adjusting for confounding variables (Model 3), women with self-report of hypertension were at greater risk for developing cognitive decline (MCI/PD) compared to normotensive individuals (HR 1.20; 95% confidence interval (CI) 1.04, 1.39; P value = 0.02) (Table 4). In detailed analyses of BP control, among women with antihypertensive medication (treated), those with BP ≥140/90mm Hg (uncontrolled BP) showed highest risk estimates for developing cognitive decline (HR 1.30; 95% CI 1.05, 1.60) compared to women without treatment (untreated) and BP <140/90mm Hg (controlled BP) at baseline. We then proceeded to compare women with treated and controlled BP to women with untreated and controlled BP (Tables 5–7). We found no significant difference in risk for cognitive decline (HR 1.15; 95% CI 0.94, 1.40, P = 0.19) (Table 7). When we compared the risk for cognitive decline in women with treated and uncontrolled BP to women with treated and controlled BP, no significant differences were observed (HR 1.08; 95% CI 0.86, 1.35).
Table 4.
Blood pressure control and cognitive decline
| Mild cognitive impairment or probable dementia | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Model 1 | P value | Model 2 | P value | Model 3 | P value | ||||||||||
| N | Cases | Hazard ratio | Lower CL | Upper CL | Sum | Hazard ratio | Lower CL | Upper CL | Sum | Hazard ratio | Lower CL | Upper CL | Sum | ||
| Hypertension | No | 3,272 | 343 | 1.00 | . | . | 0.005 | 1.00 | . | . | 0.006 | 1.00 | . | . | 0.02 |
| Yes | 3,154 | 410 | 1.23 | 1.06 | 1.42 | . | 1.23 | 1.06 | 1.43 | . | 1.20 | 1.04 | 1.39 | ||
| Treatment with antihypertensive medication and blood pressure | No treatment and BP <140/90 (untreated, controlled) | 2,979 | 303 | 1.00 | . | . | 0.007 | 1.00 | . | . | 0.01 | 1.00 | . | . | 0.08 |
| No treatment and BP ≥140/90 (untreated, uncontrolled) | 1,068 | 128 | 1.07 | 0.87 | 1.32 | . | 1.08 | 0.88 | 1.33 | . | 1.07 | 0.87 | 1.32 | . | |
| Treatment and BP < 140/90 (treated, controlled) | 1,323 | 175 | 1.25 | 1.04 | 1.51 | . | 1.26 | 1.04 | 1.52 | . | 1.19 | 0.98 | 1.45 | . | |
| Treatment and BP ≥ 140/90 (treated, uncontrolled) | 1,056 | 147 | 1.38 | 1.13 | 1.69 | . | 1.38 | 1.12 | 1.69 | . | 1.30 | 1.05 | 1.60 | . | |
Model 1 adjusted for age, race, education, baseline 3MSE, and WHI menopausal hormone therapy arm.
Model 2 adjusted for age, race, education, WHI menopausal hormone therapy arm, baseline 3MSE, alcohol, smoking status, physical activity, diabetes status, BMI, depression, and total energy intake.
Model 3 adjusted for age, race, education, WHI menopausal hormone therapy arm, baseline 3MSE, alcohol, smoking status, physical activity, diabetes status, BMI, depression, total energy intake, and history of cardiovascular disease.
Abbreviation: BP, blood pressure; CL, confidence limit.
Table 5.
Blood pressure control and mild cognitive impairment
| Mild cognitive impairment | |||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Model 1 | Model 2 | Model 3 | |||||||||||||||
| N | Cases | Annualized % | Mean fup (year) | Hazard ratio | lower CL | upper CL | P value | Hazard ratio | lower CL | upper CL | P value | Hazard ratio | lower CL | upper CL | P value | ||
| Hypertension control | No treatment and BP <140/90 (untreated, controlled) | 2,979 | 186 | 0.63 | 9.97 | 1.00 | . | . | 0.002 | 1.00 | . | . | 0.007 | 1.00 | . | . | 0.07 |
| Treatment and BP < 140/90 (treated, controlled) | 1,323 | 127 | 1.05 | 9.11 | 1.45 | 1.15 | 1.82 | . | 1.39 | 1.10 | 1.77 | . | 1.25 | 0.98 | 1.60 | . | |
| Treatment with antihypertensive medication and blood pressure | treatment and BP < 140/90 (treated, controlled) | 1,323 | 127 | 1.05 | 9.11 | 1.00 | . | . | . | 1.00 | . | . | . | 1.00 | . | . | 0.36 |
| No treatment and BP ≥140/90 (untreated, uncontrolled) | 1,068 | 85 | 0.84 | 9.45 | 0.76 | 0.58 | 1.01 | 0.11 | 0.77 | 0.58 | 1.02 | 0.14 | 0.83 | 0.62 | 1.10 | . | |
| Treatment and BP ≥ 140/90 (treated, uncontrolled) | 1,056 | 100 | 1.10 | 8.62 | 1.01 | 0.77 | 1.31 | . | 0.99 | 0.76 | 1.30 | . | 1.00 | 0.76 | 1.30 | . | |
Model 1 adjusted for age, race, education, baseline 3MSE and WHI menopausal hormone therapy arm.
Model 2 adjusted for age, race, education, WHI menopausal hormone therapy arm, baseline 3MSE, alcohol, smoking status, physical activity, diabetes status, BMI, depression, and total energy intake.
Model 3 adjusted for age, race, education, WHI menopausal hormone therapy arm, baseline 3MSE, alcohol, smoking status, physical activity, diabetes status, BMI, depression, total energy intake, and history of cardiovascular disease.
Abbreviation: BP, blood pressure; CL, confidence limit.
Interactions on the effect of sodium intake based on FFQs on the risk for MCI/PD were examined in women with hypertension or antihypertensive medication at baseline (Table 8 and 9). Sodium intake >1,500mg/day tended to increase the risk for MCI/PD in women with hypertension (HR 1.24; 95% CI 1.02, 1.52) and antihypertensive medication (HR 1.19; 95% CI 0.97, 1.46), whereas sodium intake ≤ 1,500mg/day did not significantly alter this risk (HR 1.23; 95% CI 0.85, 1.78 and HR 1.18; 95% CI 0.81, 1.71). Formal tests for interaction were not significant.
As determining sodium intake by FFQ has methodological limitations,27 we additionally examined potential interactions using corrected dietary self-report data of sodium intake (Supplementary Tables 1 and 2). After applying calibration equations based on 24-hour urine excretions method, the exposure distribution of our study sample changed reflecting higher actual sodium consumption than as assessed by FFQs. Thereafter, 89% of participants were calculated to consume between 1,501–2,999mg and 11% more than 3,000mg of sodium/day. Sodium intake >2,300mg/day was associated with higher risk for cognitive decline in women with hypertension (HR 1.28; 95% CI 1.08, 1.51) whereas sodium intake <2,300mg/day did not significantly increase this risk (HR 1.56; 95% CI 0.97, 2.52). Again, formal tests for interaction were not significant.
DISCUSSION
Our study suggests that hypertension is related to the development of cognitive decline in elderly women, which is consistent with mid-life data.2 In detailed analyses of BP control, we compared women with or without antihypertensive medication and various BP levels. We found that among women on antihypertensive medication, those with uncontrolled BP were at greater risk for cognitive decline compared to those without antihypertensive medication and controlled BP (i.e., non-hypertensive women).
Excessive sodium intake is associated with the incidence and severity of hypertension while dietary modifications restricting sodium consumption have resulted in significant BP reductions.7,34 Given the benefits of sodium reduction on cardiovascular risk, the American Heart Association currently recommends sodium intake to be less than 1,500mg/day for the entire US population.12 The US Department of Health and Human Services sets a maximum limit of 2,300 mg/day for sodium for general population and 1,500mg/day for certain groups at risk including individuals above 51 years of age.12 Our analyses based on sodium intakes derived from FFQs revealed that although sodium intake >1,500mg/day was associated with an increased risk for cognitive decline in hypertensive women or women with antihypertensive treatment, tests for interaction were not significant. As FFQs may not adequately represent actual sodium intake,32 we additionally corrected our sodium intake data based on 24-hour urine excretions.28 Again, no significant interaction by sodium was observed. Finally, we investigated if sodium intake was the primary factor for predicting cognitive decline and hypertension a potential modifier but we did not detect a significant association (data not shown).
In spite of the lack of strong epidemiologic evidence for an association of sodium intake and cognitive decline,14 patho-physiological mechanisms may suggest that such a relationship exists. Excessive sodium intake elevates the risk for (silent) strokes largely mediated by BP elevations.35,36 Independent of BP changes, sodium loading increases oxidative stress, endothelial dysfunction and thereby promotes vascular aging.35,36 Both, multiple microscopic infarcts and brain regions characterized by inflammation and oxidative stress frequently coexist in elderly brains with vascular cognitive impairment.2 Whether the observed associations of vascular risk factors with cognitive decline are due to toxic effects of vascular factors on the microcirculatory system of susceptible brain regions, some other process, or that the occurrence of vascular risk factors and cognitive decline are independent but convergent disease processes remains uncertain.2 To this point, there is growing evidence proposing a synergism between the pathogenic mechanisms of cognitive dysfunction, vascular risk factors and atherosclerosis.2 However, in the light of the current debate on sodium intake and cardiovascular events,37,38 more research is warranted to examine if a potential relationship between sodium intake and cognitive decline truly exists and if so, if a linear or J-shaped relationship can be assumed.7,38,39
Strengths of our analysis include a large sample size and a structured study design with long follow-up. Dietary self-report data on sodium intake were corrected for measurement errors using calibration equations.28 Outcome variables were confirmed and centrally adjudicated as well as several confounding factors were available. Our study also exhibits several methodological weaknesses. Although we excluded women with stroke, we cannot evaluate the effect of silent cerebrovascular events over the course of the study given the absence of regular magnetic resonance neuroimaging. Exposure variability was limited as sodium intake was only determined at baseline. On the other hand, behavioral dietary changes are very challenging to accomplish and to maintain on the individual level and significant changes in the overall population are unlikely to occur. The role of antihypertensive medication is difficult to elucidate since those with the highest BP at baseline were less likely to be taking antihypertensive medication while those who took such medications may have had lower BP. Also, we do not have sufficient data available to specifically examine whether some antihypertensive drugs are associated with more risk for cognitive dysfunction than others. Furthermore, residual confounding cannot be excluded as we are missing information on, e.g., renal functioning of our participants. Last, reverse causality may have influenced our study results because of medical advice or an illness-related reduction in food consumption. As our study population consisted of relatively healthy postmenopausal women we believe that this potential bias is rather low. Conversely, due to our healthy study population external validity may be limited which may underestimate the true association in the general population.
In conclusion, among elderly postmenopausal women, those with antihypertensive treatment and uncontrolled BP showed highest risk estimates for developing cognitive decline compared to non-hypertensive women. Sodium intake did not modify the risk for cognitive decline in women with hypertension or receiving antihypertensive medication.
SUPPLEMENTARY MATERIAL
Supplementary materials are available at American Journal of Hypertension (http://ajh.oxfordjournals.org).
DISCLOSURE
The authors declared no conflict of interest.
Supplementary Material
ACKNOWLEDGMENTS
We thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: https://cleo.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf.
The WHI program is funded by theNational Heart, Lung, and Blood Institute,National Institutes of Health, andU.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C.
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