Antihypertensive Medication and Dementia Risk in Older Adult African Americans with Hypertension: A Prospective Cohort Study

Hypertension is one of the most common chronic diseases in older adults, and its prevalence is particularly high in African Americans. In the United States, compared to adults aged 18–39 years, the prevalence of hypertension in adults older than 60 years is more than eight times as great; among all adults, the prevalence is 41% for African Americans and 28% for whites.1^, 2 Studies showed that most older adults were aware of their hypertension (83%) and receive treatment (76%), but only 52% of hypertensive adults had controlled blood pressure; these results were similar for African Americans and whites.1 As hypertension is associated with an increased risk for dementia, one explanation for the greater risk of dementia in African Americans versus whites may be their higher rates of hypertension.3^–7 This risk is especially salient given that dementia in African Americans is of mixed pathology, often involving vascular factors.8^–11 Importantly, the onset of dementia results in an inexorable decline in cognitive function and long-term disability.

Effective control of hypertension with antihypertensive pharmacotherapy is an important intervention for mitigating the deleterious effects of high blood pressure leading to dementia.12 In a previous work, we determined that antihypertensive medications preserved cognitive function in a community-based cohort of African Americans in Indianapolis, Indiana.13 The odds ratio of incident cognitive impairment was 0.62 (95% CI 0.45–0.84) in subjects prescribed antihypertensives compared to those who were not. However, our study did not assess the onset of dementia, and blood pressure measurements were not sufficient to assess the effects of blood pressure and antihypertensive prescribing on the onset of dementia. The original cohort, established in 1992, was supplemented with a larger number of older adult African Americans and more complete assessment of blood pressure. In the present study, therefore, we aimed to assess the longitudinal effects of antihypertensive medications and blood pressure on the onset of dementia in a cohort of non-Hispanic African Americans with a diagnosis of hypertension spanning up to 24 years.

Of the 1236 hypertensive participants without dementia at baseline, 114 (9%) developed incident dementia during follow-up evaluations. In Table 1, we include comparisons of participant characteristics, medical conditions, and blood pressure measures between the incident dementia and non-dementia groups. Individuals with incident dementia were significantly older at baseline, with fewer years of education, were more likely to be carriers of the APOE ε4 allele, and had higher initial systolic blood pressure than those who were not diagnosed with dementia. However, there were no statistically significant differences between the groups with respect to the remaining variables compared in Table 1.

In Table 2, we compare the same set of participant characteristics between those treated with antihypertensive medication and those not treated. Individuals prescribed medications had significantly higher proportions of comorbid conditions than participants with untreated hypertension. Despite the greater burden of cardiovascular and other comorbid diagnoses in those treated with antihypertensives, mortality was higher in the untreated group, possibly from events associated with elevated blood pressure. The Kaplan–Meier plot (see Fig. 1) shows the temporal distributions of incident dementia for participants prescribed antihypertensive medication and those who were untreated. Inspection of the curves shows separation at about 5 years that continues through the course of 15 years (p = 0.0078).

In Table 3, we present results from Cox models for any antihypertensive treatment and time to dementia while adjusting for demographic variables and comorbid medical conditions. Individuals prescribed any antihypertensive medication were found to have a significantly reduced risk of dementia (HR = 0.57, 95% CI 0.37–0.88, p = 0.0114) compared to untreated hypertensive participants. None of the medical conditions considered were significantly associated with dementia risk. A somewhat unusual finding was that the risk of dementia was lower in participants with a diagnosis of cancer (HR = 0.61, 95% CI 0.41–0.90, p = 0.0133). In a subset of patients who consented to blood sample collection (n = 707), we further adjusted the model by APOE ε4 carrier status. Individuals prescribed any antihypertensive medication still showed a lower risk of dementia (HR = 0.65, 95% CI 0.38–1.12, p = 0.12) than untreated hypertensive participants, but the result was no longer significant. When this analysis was repeated including a variable indicating suboptimally treated blood pressure (> 140 mmHg systolic or >90 mmHg diastolic), the effect of antihypertensive medication was no longer statistically significant (HR = 0.65, 95% CI 0.32–1.30, p = 0.2217; see Table 3). This latter effect suggests that once we included the presence of suboptimal treatment in the Cox model, the association between antihypertensive medication and incident dementia risk was no longer significant. A propensity-adjusted Cox model using variables in Table 3 also revealed a significantly reduced risk of dementia (HR = 0.33, 95% CI 0.14–0.80, p = 0.0135).

Online Supplementary Table 1 contains the results of the multiple Cox proportional hazards regression model for antihypertensive subcategories. For each antihypertensive type, the overall effect of the drug was to prevent or delay progression to dementia, with the exception of alpha-beta blockers and central adrenergic agonists. When these analyses were repeated including a variable indicating suboptimally treated blood pressure, the effect of each antihypertensive medication was no longer statistically significant, with the exception of loop diuretics (HR = 0.36, 95% CI 0.15–0.87, p = 0.0233; see Table S2 in the Online Supplementary Appendix). Thus, with the exception of loop diuretics, poorly controlled blood pressure—i.e. ineffective treatment—diminished the cognitive preservation effects of the drug.

We studied the effects of antihypertensive treatment on the risk of dementia over a period of up to 24 years in a cohort of 1262 African Americans with hypertension in the IIDP. We found that, compared to untreated participants, those prescribed antihypertensives had a 43% lower risk of dementia (HR = 0.57, 95% CI 0.37–0.88, p = 0.0114). These effects were consistent for commonly used antihypertensive medications, an important consideration when prescribing for optimal medication effectiveness and cost considerations such as brand name versus generic. When taking into account the effect of poorly controlled hypertension—i.e. blood pressure consistently >140 mmHg systolic or >90 mmHg diastolic—the risk of dementia was almost twice as great (HR = 1.78, 95% CI 1.11–2.86, p = 0.0166), and the effect of antihypertensive medication decreased to a 35% reduction in dementia risk, which was no longer statistically significant (HR = 0.65, 95% CI 0.32–1.30, p = 0.12217). We interpret these findings as suggesting that the risk of dementia is largely due to blood pressure control, regardless of the antihypertensive drug class(es) prescribed.

The results of the present study are consistent with our earlier findings in the IIDP cohort investigating the effect of antihypertensive medications on incident cognitive impairment. In the previous study, we found that antihypertensive medications reduced the odds of incident cognitive impairment in the IIDP African American cohort by 38% (OR = 0.62, 95% CI 0.45–0.84).13 However, we did not have sufficient blood pressure data to determine the effect of blood pressure for the various antihypertensive medications that had been prescribed.

Our present results are also consistent with studies of African Americans by colleagues from the Atherosclerosis Risk in Communities (ARIC) study, which assessed dementia and cognitive decline in both white and African American participants.3^, 4 However, the data comparing the risk of dementia and cognitive decline in longitudinal cohorts is conflicting. Alonso and colleagues found a higher risk of hospitalization with dementia in African Americans in the ARIC study, which included 2619 African Americans (age-adjusted HR = 2.5, 95% CI 1.9–3.3) and 8532 whites (age-adjusted HR = 1.0, 95% CI 0.7–1.3), presumably due to a greater overall burden of cardiovascular disorders (hypercholesterolemia, smoking, diabetes, and hypertension).3 However, dementia hazard ratios for hypertension were similar between African Americans (1.7) and whites (1.6). More recently, Gottesman and colleagues determined changes in cognitive scores in ARIC participants over the course of 20 years, and found a significant decline in cognitive scores in participants with hypertension that was greater in whites than African Americans and greater in those not prescribed antihypertensives versus those who received antihypertensives.4 In contrast, Katz and colleagues found that race was a significant risk factor for mild cognitive impairment but not for dementia in participants 70 years of age and older in the community-based Einstein Aging Study, after controlling for sex and education.26

Some investigators have suggested that certain classes of antihypertensive drugs may have greater neuroprotective effects than others.27^–29 However, we found little evidence (with the exception of loop diuretics) for such effects across commonly used antihypertensive medications. It is possible that the greater natriuretic potency of loop diuretics contributes further to reducing blood pressure. A recent meta-analysis of risk factors for Alzheimer’s disease suggests a general protective effect for various drug classes including antihypertensives, estrogen, nonsteroidal anti-inflammatory drugs, and statins.7 Collectively, these drugs could play some role in protecting against a variety of cardiovascular insults that might otherwise contribute to cognitive changes and dementia in susceptible persons such as those with mixed-pathology dementia.8

Differences among antihypertensive drugs may also reflect patient adherence. Poon and colleagues presented data suggesting that, in addition to a higher prevalence of hypertension in African Americans than whites, poorer adherence to antihypertensive medication may contribute to risk of dementia.30^, 31 Ritchey and colleagues also found poorer adherence in African Americans in a study of Medicare Part D beneficiaries.32 While it is possible that adherence to and tolerance of antihypertensives may be better for some drug classes than others, our results suggest that the key to preventing dementia is blood pressure control. Patients who progressed to dementia may have had more erratic medication adherence patterns, but no participants had dementia at baseline, and medication use was assessed within the period before diagnosis of dementia. Placebo effects cannot be ruled out in our study.

The lower risk of dementia found for participants with cancer (HR = 0.61) has been reported with similar effect sizes in other dementia cohorts (HR = 0.65)33 and in a recent meta-analysis of cohort studies (HR = 0.63).34 This reduced risk in individuals with cancer could represent a survivor effect or diagnostic bias, or it could be explained by a protective effect of cancer chemotherapy, but is a finding that is beyond the scope of the present study.

Our study has several limitations. Unfortunately, we do not have a sufficient number of participants with pure vascular dementia for a separate model. However, we conducted additional analyses of stroke and non-Alzheimer's dementia, and found that the overall effect size for the use of any antihypertensive medication was unaffected. We also focused our results on treated versus untreated hypertensive African Americans in our IIDP cohort, which resulted in a smaller cohort for study, and the effects of some of the less frequently prescribed subclasses of antihypertensives could not be reliably determined. It may seem unusual that there are patients with hypertension who are not receiving an antihypertensive medication. However, a recent National Health and Nutrition Examination Survey (NHANES) indicated that 24% of patients with hypertension were not receiving an antihypertensive agent.1 Others have had similar findings, including the Atherosclerosis Risk in Communities Neurocognitive Study, in which only 78.7% of white and 82.2% of African American participants with hypertension were being treated with antihypertensives.4 Presumably, patients who were not receiving medical treatment had milder hypertension managed with lifestyle modifications such as weight loss or low-sodium diets.12 In addition, some of the subclasses, such as ACE inhibitors and beta blockers, could have been used to treat other disorders in addition to hypertension. Nonetheless, the effects of these medications were generally consistent but sensitive to the inclusion of an indicator variable for poorly controlled blood pressure. Furthermore, our study data now span up to 24 years, with consistently rigorous screening and neurological assessment of cognitive impairment and dementia. Another limitation, which is faced by many cohort studies in the elderly population, is the possibility of differential dropout due to death, which may threaten the validity of the random censoring assumption required for the modeling approach. Additional models using semi-competing risk models may be required to adequately determine whether our results would change after adjusting for death.

While the rates of dementia are declining in the United States despite increases in cardiovascular comorbidities, African Americans have a disproportionate share of cardiovascular risk factors for its development.11 Control of hypertension is a key preventive intervention for reducing the risk of dementia as well as other cardiovascular insults such as myocardial infarction and stroke. Studies published to date have predominately focused on hypertension at mid-life and dementia risk, whereas our cohort participants were elderly at the time of study enrollment. Thus the results of the present study extend these earlier observations by investigating the association between hypertension later in life and risk of dementia, and the importance of reducing blood pressure with effective pharmacotherapy to prevent the onset of dementia even in older adults with hypertension.

Control of blood pressure in older adult African American patients with hypertension is a key intervention for preventing dementia, with similar benefits from most of the commonly available antihypertensive medications.