In a study that spanned two and a half decades and looked at data from more than 4,700 participants, Johns Hopkins researchers have added to evidence that abnormal blood pressure in midlife persisting into late life increases the likelihood of developing dementia.
Although not designed to show cause and effect, the study suggests that maintaining a healthy blood pressure throughout life may be one way to help decrease one’s risk of losing brain function.
“Our results suggest that one’s blood pressure during midlife may influence how blood pressure later in life relates to dementia risk,” says Keenan Walker, Ph.D., assistant professor of neurology at the Johns Hopkins University School of Medicine.
“We found that individuals with high blood pressure in midlife may benefit from targeting their blood pressure to normal levels in later life, as having blood pressure that is too high or too low in late life may further increase dementia risk.”
In their study, they found that those people with the high blood pressure condition hypertension during middle age and during late life were 49% more likely to develop dementia than those with normal blood pressure at both times.
But, putting one at even greater risk was having hypertension in middle age and then having low blood pressure in late life, which increased one’s dementia risk by 62%.
The findings were published Aug. 13 in JAMA.
High blood pressure was considered any measurement more than 140/90 millimeters of mercury, whereas low blood pressure was defined as less than 90/60 millimeters of mercury.
A cognitive exam, caregiver reports, hospitalization discharge codes and death certificates were used to classify participant brain function and determine cognitive impairment.
High blood pressure can be genetic, but can also be the result of not enough exercise and poor diet.
As people age, the top blood pressure number (systolic) oftentimes increases while the bottom number (diastolic) can decrease due to structural changes in the blood vessels.
Walker says dementia itself may lead to a lowering of blood pressure, as it may disrupt the brain’s autonomic nervous system. Stiffening of the arteries from disease and physical frailty can also lead to low blood pressure in late life.
According to the Centers for Disease Control and Prevention, 75 million people in the U.S. have high blood pressure, and high blood pressure can raise the risk for heart disease, as well as other health conditions.
Already an established risk factor for cardiovascular and cerebrovascular disease [3–6], emerging evidence suggests that hypertension may also play an important role in the development of cognitive decline, Alzheimer’s disease, and vascular dementia [7–9].
Because hypertension is a modifiable risk factor, it represents a potentially important mechanism through which the prevention or delay of age-related cognitive disorders may be possible.
For this reason, understanding hypertension’s role in the development and progression of age-related cognitive decline and dementia has been a research priority over the last two decades.
Although a great deal has been learned from epidemiological studies, there is still little consensus about the effectiveness of treating hypertension to prevent or slow cognitive decline.
What is clear, however, is that the connection between blood pressure (BP) and cognitive function is biologically complex and still not fully understood.
The goal of this review is to provide an overview of the research that has contributed to the understanding of the connection between BP and cognitive function, paying particular attention to recent findings.
In doing so, this review will first provide an overview of what is known about the connection between hypertension, cognitive function, Alzheimer’s disease, and vascular dementia.
Second, the neurobiological changes associated with hypertension will be described, and the research that demonstrates how these biological processes influence neuronal function will be highlighted.
Lastly, the findings from clinical trials designed to assess the effectiveness of antihypertensive agents for the prevention or delay of cognitive decline will be summarized.
Methodological considerations and specific recommendations for future research will also be discussed. Although this review focuses on the topic of hypertension and cognitive function, the link between low BP and cognition will also be discussed.
Hypertension and cognitive function
Cross-sectional and longitudinal observational studies
Over the last several decades the link between hypertension and cognitive function has been examined across many age groups.
Although much of this research has focused on understanding the relationship between BP and cognition in older adults, the group most likely to experience cognitive decline, studies which assess BP starting in middle-age and follow participants forward until they reach older ages have also been especially informative.
Multiple epidemiological studies have demonstrated that elevated BP in the 4th and 5th, decade of life, particularly untreated hypertension, increases the risk for cognitive impairment 20–30 years later (see Table 1) [10–12].
Because confounding variables, such as education and socioeconomic status, are less likely to affect cognitive change (compared to baseline cognitive abilities) , studies which show an increased rate of cognitive decline over time among hypertensive adults provide especially strong evidence for the deleterious effects of high BP.
Hypertension among individuals in their 70s has also been identified as a risk factor for mild cognitive impairment (MCI) – a state of subtle cognitive decline that is believed to precede the onset of dementia [24,25].
In contrast, studies that include individuals in their 8th, 9th, and 10th decade of life have largely either failed to find such an association [26,27] or have found high BP to be protective against cognitive impairment [28,29].
Together, these results suggest that the relationship between cognition and BP in late-life may be age dependent .
Inverted U- or J-shaped curves may most accurately represent the relationship between BP and cognition among octogenarians and nonagenarians, as both low BP and extremely high BP (systolic blood pressure (SBP) >160mmHg) have been linked to cognitive impairment in this age group [28,31–33].
While individuals who develop hypertension earlier in life are likely to be subjected to the deleterious neurological effects of hypertension for many decades, this is not the case for individuals who develop hypertension much later.
The strong associations found between midlife hypertension and late-life cognitive abilities supports the notion that hypertension duration and chronicity in adulthood may be especially important determinants of cognitive impairment in elderly individuals. Perhaps the strongest support for this hypothesis comes from a longitudinal study which found that a longer duration of time between hypertension initiation and cognitive testing is associated with reduced cognitive abilities independent of age .
In particular, longitudinal studies suggest that middle-aged adults with prolonged hypertension and elevated systolic blood pressure (SBP) over a period of 25–30 years are at an exceptionally high risk for cognitive impairment later in life [17,18].
Thus, studies with a longer period between the initiation of BP monitoring and subsequent cognitive assessment may be better able to detect the effects of high BP on neurocognitive outcomes.
The trajectory of blood pressure changes from midlife into older age may also be important, as the combination of hypertension in midlife and low diastolic blood pressure (DBP) in late-life has been associated with smaller brain volumes and poorer cognitive outcomes among older adults .
Individuals who develop hypertension before middle adulthood may also be at particularly high risk for cognitive impairment, as a number of studies have found associations between high BP, cognitive deficits, and reduced academic functioning in children, adolescents, and young adults [35–40].
Irrespective of age, the cognitive domains that appear most vulnerable to hypertension are executive functioning and information processing speed. Both cognitive processes rely heavily on the integrity of frontal and subcortical brain structures which may be most vulnerable to the effects of hypertension.
Blood pressure variability
Although a number of studies have demonstrated a connection between orthostatic hypotension and cognitive function, with worse performance in the setting of orthostasis [45–48], others have failed to replicate this finding [49–51].
Ambulatory blood pressure measurement (ABPM) has been used in a number of studies to more accurately capture short-term, daily BP variability, which may reflect autonomic dysfunction or increased arterial stiffness, among other etiologies.
Using ABPM, elevated 24-hour mean BP, 24-hour BP variability, and reduced nocturnal dipping (a natural reduction of night-time BP) have each been identified as potential risk factors for cognitive impairment [11,52–54]. B
ecause autonomic dysfunction occurs in the early phase of several neurodegenerative disorders , it is difficult to determine whether cognitive deficits found in individuals with potential sequelae of autonomic dysfunction (e.g., BP variability and orthostatic hypotension) are the result of underlying neurodegenerative changes or the direct effect of transient drops in BP.
Additional insights into the relationship between hypertension and cognition have emerged through genetic studies.
A polymorphism in the ACE gene, a gene which regulates BP through its effects on angiotensin converting enzyme (ACE) activity , has been linked to both cognitive function  and the presence of neuroimaging abnormalities [58,59]. Middle-aged and older adults who carry an allele that codes for the high activity variant (D) of the ACE I/D polymorphism show greater levels of cognitive impairment and cognitive decline [57,60–62]. Unexpectedly, other studies have found the low activity allele (I) of the ACE I/D polymorphism to confer increased risk for dementia [63,64].
Polymorphisms in another gene, AGTR1, which codes for the angiotensin-II type 1 receptor, also an important part of the regulation of BP, have been associated with reduced prefrontal and hippocampal volume , reductions in hippocampal volume over time, and poorer memory in older adults .
Additional evidence suggests that specific genetic variants may interact with hypertension to promote or buffer against the effects of elevated BP on cognitive function and brain structural integrity. Two Alzheimer’s disease risk genes that have also been associated with cognitive function in nondemented individuals, Apolipoprotein E (APOE) and Clusterin (CLU), appear to modify the effect of hypertension on cognitive function . For example, multiple studies have found that hypertension is only associated with cognitive deficits in individuals who possess a copy of the ε4 allele of the APOE gene [68,69].
Dementia risk and hypertension
Several forms of cardiovascular disease have been identified as risk factors for both Alzheimer’s disease and vascular dementia [70–73], which together account for the majority of dementia cases worldwide [74,75].
Alzheimer’s disease, cerebrovascular disease, and cardiovascular disease have shared genetic contributions [76,77], and approximately 50% of individuals diagnosed with Alzheimer’s disease display significant cerebrovascular pathology on autopsy [78,79].
Despite significant evidence for the role of cardiovascular disease in the pathogenesis and progression of Alzheimer’s disease, the association between hypertension and Alzheimer’s disease is still not well understood.
Although a consistent relationship between elevated DBP at midlife and incident Alzheimer’s disease has been demonstrated [7,83,84], evidence for an association between midlife SBP and incident Alzheimer’s disease has been conflicting [84–88]. What is clear is that late-life hypertension does not appear to be a risk factor for incident Alzheimer’s disease [72,88–93].
In fact, multiple studies suggest that abnormally low DBP in late-life may increase one’s risk for Alzheimer’s disease [91,94–98]. Some, but not all, have argued that this inverse relationship between late-life DBP and Alzheimer’s disease risk results from a tendency for BP to decline concurrently with the onset and progression of dementia [90,99,100].
Together, previous findings suggest that the combination of high BP in midlife followed by low BP in late-life may place individuals at especially high risk of developing Alzheimer’s disease. However, few studies have examined this hypothesis directly .
Because hypertension is a known risk factor for cerebral small vessel disease  and stroke , hypertension is often considered a risk factor for vascular dementia, a form of cognitive decline resulting from small- or large-vessel cerebrovascular disease [9,103].
However, only a handful of studies have directly examined the relationship between hypertension and vascular dementia. Although previous research supports the relationship between midlife hypertension and the development of vascular dementia [8,83,85,104–106], it is unclear whether there is an association between late-life hypertension and vascular dementia, as findings have thus far been conflicting [72,89,91,107].
Compared to the associations between midlife hypertension and incident Alzheimer’s disease, the associations found between midlife hypertension and incident vascular dementia tend to be more robust and consistent [8,85,108].
However, because patients are more likely to develop mixed Alzheimer’s and vascular dementia than pure forms of one or the other, this distinction may not be meaningful.
Pathophysiology of hypertension as it relates to cognitive decline
Evidence from neuroimaging and biomarker studies
Neuroimaging has played a pivotal role in advancing the understanding of how BP influences cognitive function and underlying brain structure.
Results from studies that have examined the relationship between BP and brain volume are largely consistent with findings from the BP and cognition studies.
In elderly populations, low SBP [116,117] and low DBP [117,118] have been associated with reduced brain volume and cortical thickness, suggesting that the relationship between BP and brain volume may age-dependent [15,119,120].
A pattern of hypertension in midlife followed by hypotension in late-life appears to be especially harmful , particularly in brain regions affected in the earliest phase of Alzheimer’s disease .
An association between hypertension and the development of Alzheimer’s disease has also been supported by research that examines Alzheimer’s disease biomarkers directly. Compared to the brains of normotensive individuals, the brains of individuals with a history of hypertension show greater levels of β-amyloid plaques, atrophy, and neurofibrillary tangles [86,122].
Similarly, hypertension has been identified as a risk factor for cortical fibrillar β-amyloid deposits [81,123,124] and reduced glucose metabolism in Alzheimer’s disease-specific brain regions [123,125] using positron emission tomography (PET) in the brains of cognitively normal middle-aged and older adults.
Consistent with these findings, one study found that individuals with abnormal plasma β-amyloid levels and elevated BP at midlife have an especially high risk of developing Alzheimer’s disease later in life .
Hypertension has also been associated with several defining features of vascular dementia and cerebral small vessel disease, including WMH volume [15,102], WMH progression [126,127], lacunar infarcts, and cerebral microbleeds [5,128–130].
Supporting the relationship between high BP and white matter pathology, findings from observational studies  and clinical trials [113,131] suggest that treatment of hypertension reduces WMH progression.
Even before the development of overt neuroimaging abnormalities, hypertension appears to be associated with reduced white matter microstructural integrity in both young and old individuals, suggesting white matter may be especially vulnerable to the deleterious effects of hypertension [132–135].
Hypertension and vascular remodeling
Emerging evidence suggests that sustained elevations in BP may cause cerebral vessel remodeling in a manner which promotes pathological brain changes and subsequent cognitive decline.
To preserve the steady low-pressure blood supply to the periphery and protect end organ microcirculation from pulsatile stress associated with hypertension, a rearrangement in vessel wall material in the form of hypertrophic remodeling of the media and vascular smooth muscle cells occurs [136–138].
This enlargement in media size causes a reduction in lumen diameter, leading to increased vascular resistance and vessel wall stiffening .
Arterial stiffening, in turn, increases arterial pulse wave velocity and pulsatile pressure, which over time causes rarefaction of downstream capillaries and further inward remodeling of vessel walls [140–142].
Hypertension promotes intracranial atherosclerosis in large intracranial arteries [142,143] and arteriolosclerosis in smaller arterioles supplying subcortical white matter and deep gray matter brain structures .
Arteriolosclerosis is a process characterized by a loss of tunica media smooth muscle cells, fibro-hyaline deposits, and thickening of the vessel wall, resulting in increased microvascular resistance.
Because the brain requires high levels of continuous perfusion throughout systole and diastole , increases in vascular resistance leave cerebral arterioles vulnerable to hypoperfusion when systemic BP is reduced [139,144]. As described below, hypoperfusion has been associated with several neurovascular changes , which together may disrupt cognition .
More information: Keenan A. Walker et al. Association of Midlife to Late-Life Blood Pressure Patterns With Incident Dementia, JAMA (2019). DOI: 10.1001/jama.2019.10575
Journal information: Journal of the American Medical Association
Provided by Johns Hopkins University