Midlife Blood Pressure Research Articles

Blood pressure and dementia - a comprehensive review.

Alzheimer's disease (AD) and vascular dementia (VaD) are important causes of cognitive decline in the elderly. As a result of an ageing population worldwide, the incidence of dementia is expected to rise exponentially over the coming decades. Vascular risk factors are implicated in the pathogenesis of both AD and VaD. Hypertension in midlife is particularly associated with an increased risk of developing dementia. One might hope the treatment of high blood pressure in midlife would reduce the risk of developing dementia, as it does the risk of stroke. Divergent results have been reported in studies examining this effect, with the evidence suggesting that certain antihypertensives confer benefits beyond others. This implies that certain drugs may have neuroprotective properties separate to their blood pressure lowering capabilities. Recent trials have added to our understanding of these relationships.

Unfavourable risk factors for type 2 diabetes mellitus are already apparent more than a decade before onset in a population-based study of older persons: from the Age, Gene/Environment Susceptibility—Reykjavik Study (AGES-Reykjavik)

We evaluated midlife risk factors of developing type 2 diabetes mellitus (T2DM) in late life in a population-based study of older persons. A cohort of 2,251 persons, aged 65-96, participated in AGES-Reykjavik in 2002-2004; all attended the Reykjavik Study 26 years earlier, at the mean age of 50. Based on glucometabolic status in 2002-2004 the participants are divided into a normoglycemic control group (n = 1,695), an impaired fasting glucose (IFG) group (n = 313) and T2DM group (n = 243). Change in risk parameters from midlife is evaluated retrospectively in these three groups. Since examined earlier 14.3% of men and 8.2% of women developed T2DM. A family history of diabetes was reported in 39.5% of T2DM compared to 19.3% in both IFG and normoglycemics. The T2DM and IFG groups currently have higher levels of fasting triglycerides, greater body mass index (BMI) and higher systolic blood pressure than normoglycemics and this difference was already apparent in midlife. In late life, two or more metabolic syndrome criteria are present in 60% of the T2DM groups compared to 25% in normoglycemic groups. T2DM with impaired cardiovascular health is more marked in women than men when compared with normoglycemics. Family history and higher levels of BMI, triglycerides and systolic blood pressure in midlife are associated with the development of T2DM in late life, suggesting risk can be evaluated long before onset. A continued rise in risk factors throughout life allows for more aggressive measures in preventing or delaying development of T2DM and its effect on cardiovascular health.

How much does hypertension affect cognition?: Explained variance in cross-sectional analysis of non-demented community-dwelling individuals in the SEARCH study

Vascular pathology impairs cognition and impaired cognition increases the risk of dementia. Hypertension is arguably the vascular risk factor that can be reverted best. Here we estimated the effect magnitude of hypertension by determining the variance in cognition explained by systolic blood pressure (sBP) in non-demented community-dwelling individuals. We recruited 525 individuals (mean age 65, range 40–85) selected from the city registry of Muenster, Germany, measured cognitive performance with a comprehensive test battery and assessed vascular risk based on glycosylated hemoglobin, serum cholesterol, high sensitive C-reactive protein, body mass index, smoking pack years, and blood pressure. Including gender and education as well as the vascular risk factors, multiple linear regression analysis for different age groups showed that in midlife age groups systolic blood pressure explained up to 11% of the variance in cognitive performance. These findings suggest that in non-demented community-dwelling individuals hypertension may account for one tenth of cognitive impairment and thus for an increased risk for dementia.

Blood pressure and the risk for dementia—A double edged sword

Alzheimer's disease (AD) and vascular dementia (VaD) are important causes of cognitive decline in the elderly. As a result of the aging population, the incidence of dementia is expected to increase substantially over the coming decades. Many studies have identified that vascular risk factors are implicated in the pathogenesis of both AD and VaD. Longitudinal studies have suggested that high blood pressure in midlife is associated with a higher incidence of both AD and VaD in later life. The association appears weaker for hypertension in later life. Some studies also suggest that hypotension; especially low diastolic blood pressure in late-life is also associated with an increased risk of AD. Long-standing hypertension may lead to severe atherosclerosis and impaired cerebrovascular autoregulation. A decline in blood pressure in later life may contribute to diminished cerebral perfusion. The subsequent ischaemic state may lead to increased cerebral β-amyloid accumulation.

The renin-angiotensin system, hypertension and cognitive dysfunction in alzheimer's disease: new therapeutic potential

Alzheimer's disease, which is the most common cause of dementia, is traditionally thought to be a neurodegenerative disorder and not of vascular origin. However, there is a growing body of evidence suggesting an association between vascular risk factors and Alzheimer's disease. Several epidemiological studies have shown that high mid-life blood pressure is related to the development of Alzheimer's disease in later life. Furthermore, the use of some kinds of antihypertensive medication has been suggested to reduce the incidence of dementia including Alzheimer's disease. Recent findings indicate that the brain has its own renin-angiotensin system, which mediates several physiological and pathological brain functions. The neurobiological links between the renin-angiotensin system and Alzheimer's disease have been investigated and become a source of interest in the pathogenesis of the disease. This review describes the relation between the renin-angiotensin system, hypertension and Alzheimer's disease, and also discusses the potential use of antihypertensive drugs acting via the renin-angiotensin system in the treatment and prevention of the disease.

Antecedent Blood Pressure, Body Mass Index, and the Risk of Incident Heart Failure in Later Life

Higher blood pressure and body mass index (BMI) are risk factors for heart failure. It is unknown whether the presence of these risk factors in midadulthood affect the future development of heart failure. In the community-based Framingham Heart Study, we examined the associations of antecedent blood pressure and BMI with heart failure incidence in later life. We studied 3362 participants (57% women; mean age: 62 years) who attended routine examinations between 1969 and 1994 and examined their systolic and diastolic blood pressure, pulse pressure, and BMI at current (baseline), recent (average of readings obtained 1 to 10 years before baseline), and remote (average of readings obtained 11 to 20 years before baseline) time periods. During 67 240 person-years of follow-up, 518 participants (280 women) developed heart failure. Current, recent, and remote systolic pressure; pulse pressure; and BMI were individually associated with incident heart failure (all P<0.001). Recent systolic pressure (hazards ratio [HR] per 1-SD increment: 1.31; 95% CI: 1.11 to 1.55), pulse pressure (HR per 1-SD increment: 1.33; 95% CI: 1.14 to 1.54), and BMI (HR per unit increase: 1.15; 95% CI: 1.08 to 1.23) were associated with heart failure risk even after adjusting for current measures. Similarly, remote systolic pressure (HR per 1 SD: 1.17; 95% CI: 1.04 to 1.31), pulse pressure (HR per 1 SD: 1.17; 95% CI: 1.06 to 1.31), and BMI (HR per unit: 1.09; 95% CI: 1.05 to 1.14) remained associated with incident heart failure after adjusting for current measurements. Higher blood pressure and BMI in midlife are harbingers of increased risk of heart failure in later life. Early risk factor modification may decrease heart failure burden.

Relation of Obesity to Cognitive Function: Importance of Central Obesity and Synergistic Influence of Concomitant Hypertension. The Framingham Heart Study

Obesity has been related to the incidence of dementia but its impact on cognitive performance in persons without dementia is less clear. We hypothesized that mid-life obesity may modulate the impact of conventional cardiovascular risk factors (CVRF) on cognitive impairment. We tested this hypothesis in the community-based Framingham Offspring Study sample. At Examination cycle 4 (1988-90) of the Offspring Cohort, indices of obesity (BMI and Waist-Hip Ratio [WHR]) and baseline CVRF levels were ascertained in 1,814 men and women, aged 40-69 years. Obesity and hypertension were related to the score on each of 8 neurocognitive tests measured at Examination 8, 12 years later (1999-2002). Midlife measures of central obesity (WHR in the uppermost quartile- Q4) and of hypertension (BP > or = 140 / > or = 90 or use of anti-hypertensive medication) were each significantly related to poorer performance on executive function & visuomotor skills (Trails B, Visual Reproductions-Immediate and Delayed Recall). Further, the relation of hypertension to neurocognitive performance was significantly modified by WHR; hypertension was not associated with neurocognitive performance in WHR Q1-Q3, but was associated with a marked adverse performance in Q4 WHR. Neither HTN nor obesity was individually or synergistically related to verbal memory (immediate or delayed recall). Executive function and visuomotor skills were differentially affected by the combined presence of midlife hypertension and Q4 WHR while measures of verbal memory function were not related to these risk factors in our sample, a pattern consistent with vascular cognitive impairment. Control of mid-life elevated blood pressure and central obesity may be strategies to reduce cognitive decline with age.

Cardiovascular disease and Alzheimer's disease: common links

Growing evidence supports a strong and likely causal association between cardiovascular disease (CVD), and its risk factors, with incidence of cognitive decline and Alzheimer's disease. Individuals with subclinical CVD are at higher risk for dementia and Alzheimer's. Several cardiovascular risk factors are also risk factors for dementia, including hypertension, high LDL cholesterol, low HDL cholesterol and especially diabetes. Moderate alcohol appears to be protective for both CVD and dementia. In contrast, inflammatory markers predict cardiovascular risk, but not dementia, despite biological plausibility for such a link. The substantial overlap in risk factors points to new avenues for research and prevention.

Midlife Pulse Pressure and Incidence of Dementia

Previous studies have shown that midlife systolic blood pressure (SBP) predicts late-life cognitive decline and incident dementia. This study explores whether this association is attributable to the pulsatile, ie, pulse pressure (PP), or the nonpulsatile component of blood pressure (BP). Data are from the Honolulu-Asia Aging Study, a community-based study of Japanese American men. Midlife BP was measured in 1971 to 1974 and dementia assessment was conducted in late-life. The 2505 men who were dementia free in 1991 and had complete follow-up data were re-examined for incident dementia in 1994 to 1996 and 1997 to 1999. Their age ranged from 71 to 93 years. Survival analysis with age as the time scale was performed to estimate the risk (hazard ratio [HR] and 95% CI) for incident dementia associated with mid- and late-life tertiles of PP and mean arterial BP, as well as SBP and diastolic BP categories. Over a mean of 5.1 years of follow-up, 189 cases (7.5%) of incident Alzheimer disease or vascular dementia were identified. After adjustment for cerebrovascular risk factors, dementia was significantly associated with SBP (HR 1.77; 95% CI, 1.10 to 2.84, for SBP > or =140 mm Hg compared with SBP <120 mm Hg), but not with PP tertiles. Limiting the analysis to those never treated with antihypertensives, high levels of all 4 BP components were significantly associated with dementia. In models with 2 BP components, only SBP remained significant in both the total sample and the never-treated subgroup (HR 2.29; 95% CI, 1.23 to 4.25, for SBP > or =140 mm Hg in total sample), whereas PP was not significantly associated with the risk for dementia. Midlife PP is not independently associated with dementia incidence. Midlife SBP is the strongest BP component predicting incident dementia.

High blood pressure was associated with cognitive function in middle-age in the Whitehall II study

Background and Objectives Research shows elevated levels of blood pressure in midlife to be linked to impaired cognitive performance in old age. However, it remains unclear if this association extends to younger age groups. The objective of this study was to examine the association between hypertension and a range of cognitive abilities in middle aged men and women. Methods Data are from the Whitehall II study. Measures of blood pressure were obtained at baseline (1985–1988) and two subsequent phases of data collection (1991–1994 and 1997–1999). Cognitive function (memory test, AH 4-I, Mill-Hill, phonemic and semantic fluency) was assessed (1997–1999) when participants ( N = 5,838) were aged 46–68 years old. Results Results show a small inverse association between both diastolic and systolic blood pressure and cognitive performance, independent of age, education, employment grade, smoking status, alcohol consumption, use of antihypertensive medication, diagnoses of diabetes, and cardiovascular disease. Similar associations were seen with prospective and cross-sectional analyses. The effect of hypertension was stronger in women, and stronger for cognitive measures assessing executive function. Conclusion Expanding on previous studies on older participants, the present study reports a small, but significant association between hypertension and poor cognitive performance in middle-aged men and women.

Obesity and Vascular Risk Factors at Midlife and the Risk of Dementia and Alzheimer Disease

Vascular risk factors play a role in the development of dementia, including Alzheimer disease (AD). However, little is known about the effect of body mass index and clustering of vascular risk factors on the development of dementia. To investigate the relation between midlife body mass index and clustering of vascular risk factors and subsequent dementia and AD. Participants of the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study were derived from random, population-based samples previously studied in a survey carried out in 1972, 1977, 1982, or 1987. After an average follow-up of 21 years, 1449 individuals (73%) aged 65 to 79 years participated in the reexamination in 1998. Dementia and AD. Obesity at midlife (body mass index>30 kg/m2) was associated with the risk of dementia and AD even after adjusting for sociodemographic variables (odds ratio [OR], 2.4 [95% confidence interval (CI), 1.2-5.1]). The association was somewhat modified by further adjusting for midlife blood pressure, total cholesterol level, and smoking (OR, 2.1 [95% CI, 1.0-4.6]) and also for apolipoprotein E genotype and history of vascular disorders (OR, 1.9 [95% CI, 0.8-4.6]). Midlife obesity, high total cholesterol level, and high systolic blood pressure were all significant risk factors for dementia with ORs of around 2 for each factor, and they increased the risk additively (OR, 6.2 for the combination). Obesity at midlife is associated with an increased risk of dementia and AD later in life. Clustering of vascular risk factors increases the risk in an additive manner. The role of weight reduction for the prevention of dementia needs to be further investigated.

Cardiovascular Risk Factors Predictive for Survival and Morbidity‐Free Survival in the Oldest‐Old Framingham Heart Study Participants

To examine whether midlife cardiovascular risk factors predict survival and survival free of major comorbidities to the age of 85. Prospective community-based cohort study. Framingham Heart Study, Massachusetts. Two thousand five hundred thirty-one individuals (1,422 women) who attended at least two examinations between the ages of 40 and 50. Risk factors were classified at routine examinations performed between the ages of 40 and 50. Stepwise sex-adjusted logistic regression models predicting the outcomes of survival and survival free of morbidity to age 85 were selected from the following risk factors: systolic and diastolic blood pressure, total serum cholesterol, glucose intolerance, cigarette smoking, education, body mass index, physical activity index, pulse pressure, antihypertensive medication, and electrocardiographic left ventricular hypertrophy. More than one-third of the study sample survived to age 85, and 22% of the original study sample survived free of morbidity. Lower midlife blood pressure and total cholesterol levels, absence of glucose intolerance, nonsmoking status, higher educational attainment, and female sex predicted overall and morbidity-free survival. The predicted probability of survival to age 85 fell in the presence of accumulating risk factors: 37% for men with no risk factors to 2% with all five risk factors and 65% for women with no risk factors to 14% with all five risk factors. Lower levels of key cardiovascular risk factors in middle age predicted overall survival and major morbidity-free survival to age 85. Recognizing and modifying these factors may delay, if not prevent, age-related morbidity and mortality.

Silent cerebral white matter lesions and cognitive function in middle-aged essential hypertensive patients

Background An association between midlife blood pressure levels and late-life cognitive impairment has been reported. Hypertension is one of the most important factors related to the presence of cerebral white matter lesions, which is a prognostic factor for the development of cognitive impairment. Studies have shown a relationship between white matter lesions and cognitive decline in elderly hypertensive patients. The aim of the present study was to evaluate cognitive function in asymptomatic middle-aged hypertensive patients according to the presence or absence of white matter lesions. Methods Sixty never-treated essential hypertensive patients (38 men, 22 women), aged 50 to 60 years (mean age, 54.4 ± 3.8 years), without clinical evidence of target organ damage, were studied. All patients underwent brain magnetic resonance imaging to establish the presence or absence of white matter lesions, using the Rotterdam criteria. Cognitive function was evaluated by a neuropsychologic test battery measuring attention, memory, intelligence, anxiety, and depression. Results Twenty-three hypertensive patients (38%) were found to have white matter lesions on brain resonance. These patients exhibited a significantly worse performance on digit span forward, a standardized measure of attention than hypertensives without white matter lesions (4.86 ± 1.14 v 5.51 ± 0.97; P = .027). Hypertensive patients with white matter lesions showed no differences on both visual and logical memory tests when compared with patients without lesions. Conclusions We conclude that the presence of silent cerebral white matter lesions in middle-aged hypertensive patients is associated with a mild decline in basic attention.

Midlife blood pressure and the risk of hippocampal atrophy: the Honolulu Asia Aging Study.

Hippocampal atrophy (HA) is usually attributed to the neurofibrillary tangles and neuritic plaques of Alzheimer disease. However, the hippocampus is vulnerable to global ischemia, which may lead to atrophy. We investigated the association of midlife blood pressure (BP) and late-life HA in a sample of Japanese-American men born between 1900 and 1919. BP was measured on 3 occasions between 1965 and 1971. In 1994 to 1996 a subsample underwent magnetic resonance imaging (MRI) of the brain. Hippocampal volume was estimated by manually drawing regions of interest on relevant scan slices; HA was defined as the lowest quartile of hippocampal volume. Also assessed on the MRI were cortical and subcortical infarcts, lacunes, and white matter hyperintensities. The risk (OR, 95% CI) was estimated for HA associated with systolic (<140 versus > or =140 mm Hg) and diastolic (<90 versus > or =90 mm Hg) BP and with antihypertensive treatment. Analyses were adjusted for sociodemographic factors, other cardiovascular risk factors, apolipoprotein E allele, and correlated brain pathology. Those never treated with antihypertensive medication had a significantly increased risk for HA (OR 1.7; CI=1.12; 2.65). The nontreated subjects with high systolic BP had an increased risk (OR=1.98; CI=0.89; 4.39) for HA. Results were similar for untreated men with high diastolic BP (OR=3.51; CI=1.26; 9.74). In conclusion, treatment with antihypertensive treatment modifies the association of BP and HA, such that high levels of BP adversely affect the hippocampus in persons never treated with antihypertensives.

Arterial Hypertension: A Cause of Cognitive Impairment and of Vascular Dementia

Arterial hypertension is a well‐documented modifiable risk factor for cerebrovascular disease and for both cerebral infarction and intracerebral hemorrhage. Recent studies indicate a relationship between high blood pressure in midlife and dementia in late life and suggest that arterial hypertension may represent a cause of vascular dementia (VaD). This paper has reviewed the main evidence of a link between arterial hypertension and vascular cognitive impairment or VaD. Brain lesions induced by hypertension, diagnostic procedures for early diagnosis of vascular cognitive impairment in at risk subjects and the need to include cognitive assessment in patient's general visits in hypertension units are discussed.

Are antihypertensive agents protective against dementia? A review of clinical and preclinical data.

In the United States, the size of the population of persons aged 65 years or older is expected to double within the next 30 years, resulting in a marked increase in the prevalence of dementia. Hypertension is a risk factor for cognitive impairment and dementia in addition to cerebrovascular morbidity and mortality. The evidence for a connection between high blood pressure in midlife and dementia in late life comes from numerous longitudinal studies. A placebo-controlled, double-blind, randomized trial involving 2,418 patients aged 60 years or older with isolated systolic hypertension demonstrated that active treatment based on the dihydropyridine calcium antagonist nitrendipine with the addition of enalapril, hydrochlorothiazide, or both if needed to control systolic blood pressure to <150 mmHg, significantly reduced not only stroke and cardiovascular complications but also the incidence of vascular dementia and Alzheimer's disease. Several trials of antihypertensive treatment are ongoing to confirm this important finding. The newer dihydropyridine calcium antagonists lacidipine and lercanidipine are effective and well tolerated in the treatment of hypertension. In animal models, these newer agents also have been shown to prevent the progression of hypertensive microvascular damage. Their neuroprotective effects offer possible unique advantages in the management of hypertension.

Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease.

Presence of the apolipoprotein E (apoE) epsilon4 allele, which is involved in cholesterol metabolism, is the most important genetic risk factor for Alzheimer disease. Elevated midlife values for total cholesterol level and blood pressure have been implicated recently as risk factors for Alzheimer disease. To study the relative importance and the putative relationship among the apoE epsilon4 allele, midlife total cholesterol level, and midlife blood pressure as risk factors for late-life Alzheimer disease. Prospective population-based study. Kuopio and Joensuu, eastern Finland. Participants were derived from random population surveys from 1972, 1977, 1982, and 1987. A total of 1449 persons (73%), 65 to 79 years of age, participated in the reexamination in 1998 (mean follow-up, 21 years). Midlife blood pressure and total cholesterol level, apoE genotype, and development of Alzheimer disease during follow-up. The apoE epsilon4 allele was an independent risk factor for Alzheimer disease, even after adjustment for midlife vascular risk factors and other confounders (odds ratio, 2.1 [95% CI, 1.1 to 4.1]). Similarly, elevated midlife values for serum total cholesterol level (odds ratio, 2.8 [CI, 1.2 to 6.7]) and systolic blood pressure (odds ratio, 2.6 [CI, 1.1 to 6.6]) were independent risk factors for Alzheimer disease, even after adjustment for apoE genotype and other confounding factors. The association between the apoE epsilon4 allele and Alzheimer disease does not seem to be mediated by vascular factors. The apoE epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for Alzheimer disease. The risk for Alzheimer disease from treatable factors--elevated total cholesterol level and blood pressure--appears to be greater than that from the apoE epsilon4 allele.

Potential for antihypertensive treatment with an AT(1)-receptor blocker to reduce dementia in the elderly.

Hypertension is an established risk factor for stroke and other cerebrovascular disorders. Both stroke and small lacunar infarcts or white matter lesions can cause cognitive impairment and dementia, and there is evidence that vascular risk factors play a major role in the development of both Alzheimer's disease and vascular dementia. Several large epidemiological studies have shown that raised blood pressure in midlife is a strong risk factor for dementia later in life; however, blood pressure often decreases following the development of dementia. The cognitive function hypothesis proposes that elevated blood pressure increases the risk of decline of cognitive function, and that this can be reversed by active lowering of blood pressure. Evidence in support of this hypothesis comes from the Syst-Eur Dementia project, and from a number of smaller studies. SCOPE (Study on Cognition and Prognosis in the Elderly) is a large prospective study involving almost 5000 elderly patients (age 70-89 years), who are randomised to receive candesartan cilexetil, 8-16 mg, or placebo. Candesartan was chosen for this study because it is effective and well tolerated in elderly patients. SCOPE should provide important information on the long-term effects of AT(1)-receptor blocker treatment with candesartan on morbidity-including effects on cognitive function-and cardiovascular mortality in elderly hypertensive patients.

Variability in midlife systolic blood pressure is related to late-life brain white matter lesions: the Honolulu-Asia Aging study.

Although white matter lesions (WMLs) on brain MRI in older persons are common, the mechanisms are unclear. Besides the associations with advanced age and high blood pressure (BP), variability in systolic BP (SBP) and the resulting changes in blood flow to the deep arteries of the brain may be contributing factors. Japanese-American men in Hawaii have participated in a long-term study of cardiovascular disease, including midlife BP measurements at 3 clinical examinations in the period from 1965 to 1974. In the period from 1991 to 1993, dementia status was added to the fourth examination, and a brain MRI was completed in a fifth examination, which was from 1994 to 1996, on a subset of 575 men, who averaged 82 years. WMLs and ventricular atrophy were determined as the upper fifth in a standardized semiquantitative measure. Excess SBP variability was defined as greater than average increases in BP measurements from up to 3 examinations over 6 years. Logistic regression was used for the association of this variability with WMLs and atrophy, controlling for age, apolipoprotein E4 status, dementia diagnosis, and history of stroke. There were significant (2-fold) increased risks for WMLs among those with moderate and high SBP variability (third and fifth quintiles compared with the lowest quintile). Those in the highest SBP variability category (the fifth quintile) also had significantly more atrophy. These SBP variability-MRI relationships suggest that variation in SBP in midlife may be a contributing factor to the development of WMLs and ventricular atrophy in late life.

Joint Effect of the APOE Gene and Midlife Systolic Blood Pressure on Late-Life Cognitive Impairment

Background and Purpose — The aim of this study was to explore the joint effect of the APOE ε4 allele and midlife systolic blood pressure (SBP) on the risk for poor cognitive function in late life. Methods — The study includes 3605 surviving members of the cohort of the Japanese-American men followed prospectively over 26 years (1965–1991) as a part of the Honolulu Heart Program. In 1965 men were aged 45 to 68 years and were living in the island of Oahu, Hawaii. For this study the sample was divided into 4 categories: normal SBP (&lt;160 mm Hg)/No ε4, as the reference category; normal SBP/ε4; high SBP/no ε4; high SBP/ε4. The relative risk (RR) of late-life intermediate and poor cognitive function relative to good function was measured by the Cognitive Abilities Screening Instrument (CASI) test. Results — After adjusting for age, education, smoking, alcohol use, and body mass index, the RR for poor cognitive function (CASI &lt;74) compared with good cognitive function (CASI ≥82) in never-treated subjects was 1.3 (95% CI 0.9 to 1.9) for the normal SBP/ε4 category, 2.6 (0.7 to 10.0) for the high SBP/no ε4, and 13.0 (1.9 to 83.8) for the high SBP/ε4. Adjustment for diabetes, prevalent stroke, coronary disease, and ankle-brachial index reduced the RR of poor cognition by 25.5% (RR 13.0 to 10.8) in those with both risk factors. In the treated group, the RR was 1.9 (0.7 to 4.5) for those with both risk factors. Conclusions — The results suggest that midlife high SBP has a stronger adverse effect on cognitive function in persons with higher genetic susceptibility, but this effect may be modified by antihypertensive treatment.