Discussion
The main findings were that individuals taking RAS-acting antihypertensive medications for at least 3 years were less likely to convert from MCI to AD and had less cognitive and functional decline than those taking non-RAS-acting antihypertensive medications. Results also show that BBB-crossing RAS-acting medications conferred greater cognitive and functional benefits than non-BBB crossing RAS-acting medications in individuals with MCI. These results did not generally differ between Caucasians and African Americans, although on three cognitive tests, African Americans benefited more than Caucasians from RAS-acting medications.
These results are consistent with a prior observational study reporting slower disease progression in individuals with AD undergoing treatment of atherosclerosis and dyslipidemia than in untreated individuals. In studies investigating conversion from MCI to AD, one study reported that treatment with any antihypertensive therapy was associated with slower disease conversion but only in participants with circulatory dysregulation. A secondary analysis of a clinical trial reported that diuretics were associated with lack of conversion from MCI to AD. Results from both studies were observed regardless of change in BP.
Some prior studies have suggested cognitive and functional benefits of BBB-crossing RAS-acting antihypertensive medications. Epidemiological, histopathological, and more recently, clinical data suggest that the RAS is involved in AD incidence and progression, potentially through direct actions on Aβ neuropathology. Another study assessed the ability of 55 different antihypertensives to reduce Aβ oligomerization in vitro in hippocampal neurons from Tg2576 AD mice and found that RAS-acting medications (valsartan) attenuated oligomeric Aβ pathology and Aβ-mediated cognitive deterioration. Two cohort studies found that centrally acting RAS-acting medications reduced cognitive decline, as assessed using the Modified Mini-Mental State Examination and decreased AD incidence more than non-centrally acting RAS-acting medications. In addition, individuals taking RAS-acting medications exhibited less amyloid accumulation and AD-related pathologic changes upon autopsy than non-RAS-acting medications.
RAS-acting medications also may have benefits in individuals with AD. In studies assessing functional ability of individuals with AD, RAS-acting medications have been associated with greater exercise tolerance and less risk of falls. A recent secondary analysis from a randomized trial showed that treatment with centrally acting RAS-acting medications reduced functional decline in individuals with AD, as measured using the CDR-SOB, more than non-centrally acting RAS-acting medications.
That the present study revealed an additional benefit of BBB-crossing RAS-acting medications on conversion rate and cognitive and functional decline in individuals with MCI may support the hypotheses that the role of the BBB in the relationship between the RAS and AD is particularly important. The contribution of BBB permeability to cognitive impairment, as well as the salutary influence of BBB-crossing RAS-acting medications on cognition, have been reported. Moreover, BBB-crossing RAS-acting medications significantly reduce ACE levels in the brain in individuals at risk for AD by virtue of parental history.
To the knowledge of the authors, this is the first longitudinal study to investigate conversion rate and the cognitive and functional effects of centrally acting RAS-acting medication use in African American and Caucasians with MCI. The first strength of this study was that participants were diagnosed with MCI at baseline. Most cohort studies and meta-analyses include cognitively normal individuals or those with established AD. Present data show that clinically significant and measurable effects of RAS-acting medication use are detectible during prodromal disease stages, which is the optimal time to start treatment. It is unlikely that BP control explains the results, because non-RAS-acting medication users had statistically better BP control than RAS-acting medication users (P < .001, Table 1). In addition to higher BP levels, RAS-acting medication users self-reported more diabetes mellitus than RAS-acting medication nonusers at baseline, suggesting that RAS-acting medication users had overall poorer vascular health (P < .001, Table 1). It is therefore unlikely that a better vascular profile drove the present results.
Another strength is the diagnostic expertise at individual ADC testing sites and the comprehensive battery of tests included. Additionally, to the knowledge of the authors, no other study has included such a large sample of African Americans in an investigation of RAS-acting medications and AD. Some research shows that African Americans are at higher risk for AD and hypertension than Caucasians, although research regarding reading level and education quality may explain some of the AD-related discrepancies. Although not observed in this study, differences typically exist in the types of BP medications prescribed to Caucasians and African Americans based on past studies of clinical efficacy and outcomes, including stroke. These differences in recommendations according to race were reiterated in the 2014 Guidelines for Blood Pressure Management. African Americans are more likely than Caucasians to be prescribed antihypertensive therapy in general and to be prescribed calcium channel blockers and diuretics, whereas Caucasians are more likely to be prescribed RAS-acting antihypertensive medications. Based on the current results, not only are centrally acting RAS-acting medications cognitively and functionally beneficial in African Americans, but African Americans may benefit more than Caucasians, as evidenced by less decline in African-American than Caucasian RAS-acting medication users on three of 10 cognitive tests. These results need further replication in larger African-American cohorts, although the demographic representativeness given the different ADC locations across the United States is a strength of this study. Targeting groups who are most at risk of AD with existing treatment options should be a priority for future AD clinical trials.
Limitations
The sample consisted of research volunteers with more education and likely better overall cardiovascular health profiles than the general population, so the results may not be generalizable, although there is no a priori reason to believe that the effect of RAS-acting medications differs between those with more or less education. Information regarding medication duration and dose was not available and should be included in future analyses, particularly because African Americans are generally prescribed higher doses of RAS-acting medications.
Future Directions
Further research, particularly clinical trials, investigating the influence of BBB-crossing RAS-acting medications on AD biomarkers during prodromal disease stages is warranted. Studies using neuroimaging and collection of cerebrospinal fluid will be particularly crucial to fully understanding the relationship between AD and the RAS, particularly in individuals with preclinical AD. Targeting populations such as women and African Americans, who are at greater risk of AD, should also be of special interest. Moreover, Phase IV clinical trials in individuals with and without hypertension at high risk of AD because of race, family history, or early cognitive dysfunction should be conducted to test whether a RAS-modifying medication could be repurposed for AD indications in high-risk populations.