The linkbetweenbloodpressure and cognitive impairment is a complex beast. Several observational investigations have studied the association between blood pressure and cognitive function and yielded mixed results.1 Various explanations suchasheterogeneity in demographic and clinical characteristicsof studypopulations have been proposed for such discrepancies.Methodological limitations of clinical trials on antihypertensive therapy in relation to cognitive outcomes have added further complexity to this issue. While a meta-analysis of placebo-controlled trials showed amarginal benefit of lowering blood pressure in reducing the risk of dementia,2 the short-term follow-up and inclusion of healthy participants with low levels of comorbidities and high levels of cognitive functioning have limited the generalizability of these findings.3 Normal regulation of blood pressure is necessary for adequate organ perfusion and prevention of vascular damage. As shown in the Figure, high blood pressure in midlife, low blood pressure in old age, and excessive blood pressure fluctuation can all contribute to cognitive impairment. Hemodynamic stress, imposed by high blood pressure, results in endothelial dysfunction and damages cerebral vessels, which ultimately impairs thestructural and functional integrityof the brain.5 It has been shown that the degree of vascular damage in the systemic and cerebral circulation is linked with lower cerebral blood flow.6 Long-lasting cerebral hypoperfusion results inneuronal energycrisis andcell death.At the same time, damage of the brain can lead to dysregulation of blood pressure and a further decline in cerebral blood flow. Therefore, what is consideredanormal or lowbloodpressure in individualswithcognitive impairmentmaynotnecessarilymeanawellcontrolledbloodpressure. Instead, itmayhinder sufficientperfusion of a damaged brain. In this issue of JAMA Internal Medicine, Mossello et al7 showed that lowerdaytimesystolic bloodpressure in 172older personswithcognitive impairmentwasassociatedwitha faster cognitivedecline. Therewasno associationbetweenother office or ambulatory measures of blood pressure and accelerated cognitive decline. When participants were stratified for antihypertensive medication use, the association was present only in the group receiving treatment (72% of the total population). As a strength, this studyhas specifically focused on patients with cognitive impairment. Furthermore, the investigators applied ambulatory blood pressure monitoring, whichmighthelp to capture the circadiancomplexityof variation in blood pressure. Nonetheless, caution needs to be exercised when interpreting the results. Given the observational design, it cannot be concluded that antihypertensive therapy is directly responsible for the link between low daily systolic blood pressure and cognitive decline. It is likely that individuals receiving antihypertensive therapy had higher loads of overt and covert cardiovascular pathologies, which could independently lead to accelerated cognitive decline. To address this issue of confounding by indication, randomized clinical trials are warranted. An increasingbodyof evidence implies that a “one size fits all” approach in antihypertensive therapy needs to be replacedwith an individualized approach based on chronological age, biological age or the degree of systemic and cerebrovasculardamage,andhemodynamicstatus.8Wethink it is time tomove from the concept of “the lower thebetter” to the concept of “hemodynamic optimization” to decelerate the pace of cognitive decline by a proper management of blood pressure. There is anurgentneed for interventional studies among high-risk groups, applying various classes of antihypertensivemedications, to shed further light on the optimal control of blood pressure in older persons with and at risk of cognitive impairment. Related article page 578 Figure. The Circuit of Blood Pressure Dysregulation and Cognitive Impairment