Hypertension and cognitive function: A review of life-course factors and disparities

Abstract

Purpose of review:

Dementia is a life-course condition with modifiable risk factors from cardiovascular (CV) origin, that disproportionally affects some race/ethnic groups and underserved communities in the U.S. Hypertension is the most common preventable and treatable condition that increases the risk for dementia and exacerbates dementia pathology. Epidemiological studies beginning in midlife provide strong evidence for this association. This study provides an overview of the differences in the associations across the lifespan, and the role of social determinants of health (SDoH).

Recent findings:

Clinical trials support hypertension management in midlife as an avenue to lower the risk for late-life cognitive decline. However, the association between hypertension and cognition differs over the life course SDoH including higher education modify the association between hypertension and cognition which may differ by race and ethnicity. The role of blood pressure variability, interactions among CV risk factors, and cognitive assessment modalities may provide information to better understand the relationship between HTN and cognition.

Summary:

Adopting a life-course approach that considers SDoH, may help develop tailored interventions to manage hypertension and prevent dementia syndromes. Where clinical trials to assess blood pressure management from childhood to late-life are not feasible, observational studies remain the best available evidence.

Introduction

Along with cardiovascular (CV) disease, late-life dementia syndromes, including Alzheimer’s Disease (AD), are among the ten leading causes of morbidity and mortality worldwide. (1,2) These conditions disproportionally affect some racial/ethnic groups as well as underserved communities in the U.S. (3,4,5*,6*) Dementia is a public health priority and a life-course condition with potentially modifiable risk factors, many from CV origin. (7,8,9**) Among older adults, hypertension (HTN) is the most common preventable and treatable condition that increases the risk for dementia and exacerbates dementia pathology. (10,11) However, evidence supports structural and functional disruption in the brain much earlier in the lifespan promoted by chronic exposure to CV risk factors (CVRF), including elevated blood pressure (BP). (12–14)

Life-course social factors like educational attainment may protect the brain from neurodegenerative processes and preserve cognitive function. (15,16,17*) Through modifying the relationship between CVRFs and cognitive function, life-course social factors offer a potential explanation by which marginalized populations are disproportionality impacted by both CV disease and cognitive impairment. (17*,18**,19,20**,21) Therefore, HTN is also a potential target for strategies to prevent and delay the onset of dementia syndromes and minimize disparities. (8)

Here, we provide an overview of the mechanisms linking HTN and cognition and the differences in this association across the lifespan. We discuss the importance of social determinants as primary contributors to disparities in HTN and cognition. We then focus on relevant gaps in knowledge, including the role of BP variability (BPV), the potential synergistic effects with other cardiometabolic risk factors, and the poor precision of traditional cognitive assessments.

The vascular hypothesis and heterogeneity of cognitive syndromes

Dementia in the elderly can result from multiple coexistent cerebral and systemic disorders. (22) Although AD is the most common dementia diagnosis, individuals with this condition often have accompanying vascular neuropathology and deficits in cognitive domains other than memory, including executive function, often thought of as predominantly related to vascular pathology. (23*–25) Vascular and AD neuropathological processes often exist side-by-side and exacerbate each other, creating a continuum of causative processes that may be more heavily weighted toward one or the other, but not entirely due to one or the other. (26,27) Recently, data-driven classification approaches have been used to examine the heterogeneity of dementia syndromes, uncovering disease subtypes characterized by distinct patterns of neurodegeneration. (23*) This has resulted in greater recognition of the mixed nature of most cognitive syndromes, leading to a re-examination of the crucial role of CVRFs in the development of cognitive impairment. (9,28)

The vascular hypothesis posits that CVRFs exposure promotes structural and functional disruption of normal hemodynamics in the brain. (29**,30*) The brain depends on cerebral blood flow (CBF) to receive energy substrates and eliminate toxic byproducts. (31) The endothelial lining of the cerebral vasculature serves as the seat of the well-known blood-brain barrier (BBB) and, together with specialized membrane transporters, regulates the transfer of molecules between blood and brain. (32) Endothelial dysfunction induced by vascular oxidative stress and inflammation promotes vascular leakage and extravasation of plasma proteins triggering axonal injury. (33) CVRF exposure commonly leads to endothelial dysfunction with particular impact on the brain. (34) The subsequent alterations in CBF contribute to the initiation and promotion of neurodegeneration and cognitive impairment; therefore, classifying dementia as purely vascular or purely AD is arbitrary and can be misleading. (35–37)

Hypertension is a proposed risk factor for BBB damage, microvascular hemodynamic instability, and neuroinflammation leading to accumulation of neurotoxic molecules, including amyloid beta (Ab) precursors (11,38,39). Exposure to elevated BP promotes microvascular damage to the brain arteries leading to endothelial dysfunction and impaired cerebrovascular autoregulation (the capacity to maintain CBF constant despite BP changes).(32,40) Chronic exposure to high BP leads to continuous disruptions in CBF, causing chronic hypoperfusion, further damaging the endothelium.(40,41) Additionally, HTN increases the risk for atherosclerosis, an independent contributor to vascular and AD pathology. (42) Arterial parameters like carotid intima-media thickness and aortic stiffness have been reliable surrogates of atherosclerosis and strongly associate with cognitive dysfunction. (43,44) Altogether, these changes result in chronic cerebral hypoperfusion, neuronal injury, and neurodegeneration, all of which are key mechanisms for the development of dementia. (45–47**)

The life-course relationship between HTN and cognitive function

The relationship between BP levels and cognitive function in observational studies differs across the lifespan. (48) In late-life, a paradoxical relationship whereby higher BP is associated with better cognitive function has been found in several studies, and leads to the question of whether elevated BP in late-life could be protective.(49–51) Indeed, in epidemiological studies among those ≥ 80 years, including the Australian Centenarian Study, the OCTO-Twin Study, and The Kungsholmen Project, higher SBP associated with better cognition. (32,51,52) Earlier in late-life (≥ 60 years old), cross-sectional cohorts like The Baltimore Study have found U-shaped associations between BP and cognition, in the ranges of SBP 90 – 200 mmHg.(49) In contrast, longitudinal analyses showed that higher SBP at baseline associated with higher rates of cognitive decline later in life (age ≥80). (49) Similarly, results from six years of follow-up in the ARIC study showed that HTN at baseline (age 50–60) was associated with cognitive decline. (13) The inconsistency of late-life findings has emphasized the importance of longitudinal measurements that align with the timing of pathophysiological processes in cognitive impairment. (53**,54**)

Longer follow-up periods better capture the influence of BP on prodromal stages beginning in midlife and demonstrate strong associations between BP and cognitive function. (9) Studies with more than 20 years of follow-up have shown that elevated SBP and HTN associate with worse cognitive performance and dementia. (55–59) Furthermore, results from the CARDIA study demonstrated that a higher burden of SBP from young adulthood is associated with worse cognitive performance as early as midlife (age ~50). (60) Thus, providing information that better demonstrates a time-dependent effect of BP on cognition.

In children and adolescents elevated BP is associated with cognitive dysfunction both during youth and later in life, likely as manifestations of target-organ damage due to disruptions in cerebral microvasculature. (61*–64) Cross-sectional results from the NHANES III study demonstrated that SBP ≥ the 90^th percentile in children 6–16 years associated with decreased performance on the Digit Span Task. (65) Similar results were found in the Generation R Study. (66) In a prospective multicenter study in the US, children ages 10–18 with uncontrolled HTN had sustained decreased performance on NP tests compared to normotensive controls after 1-year. (67) The long-term effects of elevated BP from childhood were demonstrated in the Young Finns Study, where a cumulative burden of higher SBP was associated with poorer performance on NP tests in midlife. (68) These findings provide evidence for the possibility of targeting BP during childhood and adolescence as a potential pathway to prevent cognitive decline.

Evidence from Clinical Trials

Most clinical trials have studied individuals in late-life when neuropathological changes may have already been established. Therefore, any BP management interventions at this point might be too late to provide benefits. (69) A recent meta-analysis of BP treatment interventions in adults of ≥60 years failed to provide evidence of benefit but also no evidence of adverse cognitive outcomes. (70) Despite this, multicenter clinical trials targeting BP control, including FINGER*, PROGRESS, and SPRINT-MIND, have shown positive results. (71**–73) The SPRINT-MIND trial found that intensive BP control (SBP <120mmHg) reduced the incidence of MCI after five years. (71**) This suggests that management of HTN in midlife may be an avenue to lower the risk for late-life cognitive decline. Still, managing BP to maintain cognitive health remains a challenge; the benefits vary from person to person, and that variability could possibly be influenced by earlier exposure to CVRFs. Given that randomized clinical trials that last the decades necessary to assess HTN treatment from childhood and late-life cognitive function are not feasible, observational studies remain the best available evidence.

Social determinants and disparities in hypertension and cognition

There are racial, geographic, and socioeconomic differences in the prevalence of HTN and dementia syndromes. (74,75*) The exact mechanisms driving such disparities and the connection between these conditions are complex. Yet, the interaction of neurobiological processes with life-course social determinants of health (SDoH) – defined as the various circumstances in which people are born, developed, and grow – are strongly implicated on the causal pathway (Figure 1.) (76,77*,78) Socioeconomic status in the US is influenced by education. (79) Together, they impact the development of vascular conditions such as HTN and late life cognitive syndromes including dementia, which is compounded by racial inequities in both conditions.

Figure 1.

Life-course factors impacting hypertension and cognition

Adapted from Glymour and Manly, 2008; Figure 1. depicts neurobiological parameters, and social factors impacting hypertension, cognitive function and the association between both across the life-course, from the prenatal period to old age. Social factors are divided according to their mediator role in the causal pathway to cognitive outcomes.

The relationship between HTN and cognitive function over the life-course may differ by race and ethnicity. (80) Individuals from five well-characterized prospective cohorts demonstrated a steeper decline in cognition among African Americans compared to their White counterparts, and the difference was eliminated when HTN was accounted for in the multivariate model. (81**) This strongly suggests that higher BP levels contributed to racial differences in late-life cognitive decline. Similar results were found in the REGARDS study. (82) In studies, with smaller sample sizes and shorter duration, differences by race were not apparent or were confined to baseline cognition rather than cognitive change. (75*) Some of these inconsistencies may result from selective survival and differential attrition, whereby African Americans with a higher burden of HTN who may be experiencing cognitive issues are lost or withdrawn from longitudinal studies. (83,84)

Education has a substantial impact on cognitive outcomes across the life-course and has been shown to modify the pathway between CVRFs and cognition. (20) Higher levels of education protect the brain through bolstering cognitive reserve or the ability to sustain better cognitive function despite brain pathology. (17*) Thus, individuals in the same age-span can have the similar levels of pathobiological indicators such as Aβ in the brain but have different cognitive outcomes. (15,17*,20).Greater cognitive reserve, associated with higher levels of education, decreases the incidence and prevalence of dementia. (86) Education may also indirectly impact cognition by promoting better lifestyle choices and greater levels of health literacy, both of which may improve the management of chronic conditions such as HTN.

In clinical trials targeting BP control, individuals from diverse backgrounds account for less than 5% of participants, and far less come from rural or segregated communities. (88) Stratification of results and consideration of SDoH are useful methodologies to better understand the relationship of BP and cognition among subgroups. However, most studies to date have failed to present stratified results and or include a more comprehensive assessment of SDoH.(71**,89,90) Community-based interventions have proven to be a critical resource in HTN management by reaching out to populations with geographic or socioeconomic access barriers to health care and might be an ideal avenue to achieve BP control to prevent cognitive impairment. (91*) These interventions are often tailored to the beliefs and traditions of specific groups and thus may be more effective for HTIN control. (75*)

Current knowledge gaps –

Blood pressure variability

Measurement of mean BP has been historically used as an indicator of risk; however, evidence supports BPV as an independent risk factor for CV events. (92–94) The dose and duration of BPV, usually measured as visit-to-visit BPV, has been strongly correlated with atherosclerotic changes and stroke, suggesting that cerebrovascular injury over time might be the primary driver for its relationship with adverse cognitive outcomes. (95*,96**) In the elderly, BPV is correlated with brain atrophy and a higher burden of white matter hyperintensities, which associate with cognitive impairment and dementia. (97) Studies aiming to disentangle the exact mechanisms linking BPV with cognitive function suggest that arterial stiffness and atherosclerosis contribute to BPV, leading to extreme fluctuation of BP levels that disrupt the continuous flow to small vessels in the brain. (98,99) As a result, the extreme pulsatility damages brain microvasculature causing endothelial dysfunction and chronic inflammation, key components of the vascular hypothesis. (101) These results support the importance of expanding from traditional in-clinic BP measurements to include ambulatory BP monitoring that can capture not only mean BP levels but also BP rhythm and BPV.

Interaction with cardiometabolic risk factors

Individuals with HTN have double the risk of presenting with obesity and diabetes mellitus (DM). In epidemiological studies, these conditions are included as covariates in regression models, but their synergistic effect with HTN across the lifespan is often not captured. (102*) The cumulative burden of elevated fasting glucose has been associated with worse NP performance across different cognitive domains, and the potential mechanisms for this association include CVRFs. (60,103) DM is also directly related to chronic kidney disease and heart failure, which exacerbate damage to cerebral microvasculature and CBF. (104) Additionally, the combination of smoking, BP, and hypercholesterolemia has been shown to predict cognitive function independent of other cardiometabolic conditions in early life. (60) These findings support the need for clinical trials, such as PREVENTABLE, that assess the impact of treating other CVRF on cognitive function.

Consistency of cognitive assessment

Single cognitive-domain assessment has received greater attention in contrast to previously used global neurocognitive score-composites. (105) The hope for domain-specific analysis is to gain an understanding of tests most sensitive to HTN that would indicate underlying vascular neuropathology. (48) In particular, impairment in the cognitive domains of processing speed and executive function have been associated with CVRFs; however, the NP tests are not specific enough to test only these domains. (60) Establishing HTN-sensitive testing could have clinical applications for early detection and treatment of cognitive decline. Data-derived NP profiles or cognitive endophenotypes have been associated with distinct underlying neuropathology and, therefore, could provide useful information regarding the underlying distribution of clinical characteristics (106,107*).

Furthermore, cultural experiences and socioeconomic factors highly influence NP test performance. Even when NP tests measure the same construct across racial/ethnic groups, individuals from socially and geographically disadvantaged environments are often misclassified.(108,109) Evidence shows that despite age and years of education adjustment, African Americans with normal cognition scored lower than their White counterparts, likely due to education quality in Southern, rural, and segregated schools.(21,110) To cope with this, considering the quality of education and the use of demographically standardized NP test scores has been strongly supported as a measure to maintain consistency in test scores across different groups. (109)

Conclusion

In summary, chronic exposure to HTN promotes microvascular damage to the brain arteries leading to BBB dysfunction, neuroinflammation, and the accumulation of neurotoxic molecules, initiating and promoting neurodegeneration and cognitive impairment. The association between HTN and cognitive function is different across the lifespan. Observational and clinical trial evidence supports midlife as a critical time window for BP management to prevent or delay cognitive decline. Marginalized populations based on race, ethnicity, or geographic location in the U.S. have the highest prevalence of HTN and dementia syndromes; thus, adequate BP control may be a potential avenue to minimize disparities. Because life-course determinants like educational quality are linked to racial inequities in cognition outcomes, adopting a life-course approach that carefully considers the impact of social determinants and the cumulative burden of BP and BPV from childhood, together with precise cognitive assessments, may help develop more effective and targeted interventions to manage BP and prevent dementia syndromes.

Key points:

• The association between hypertension and cognitive function differs across the lifespan.

• Midlife is a critical time window for hypertension management to prevent or delay cognitive decline.

• Adequate blood pressure control may be a potential avenue to minimize disparities

• Observational studies remain the best available evidence to assess the benefits of hypertension control from youth in late-life cognition.