Rollercoaster blood pressure: an Alzheimer's disease risk factor?

Dementia is a major public health threat affecting over 50 million people worldwide and growing at an alarming rate of 9.9 million new diagnoses each year.¹ Despite the recently-described reduction in incidence, the number of dementia patients is estimated to triplicate by 2050, due to the aging of the world population and the lack of disease modifying treatments.¹ Recent evidence suggests that hypertension contributes significantly to the development and progression of the two most common types of dementia: Alzheimer disease (AD) and vascular cognitive impairment-dementia (VaD).² However, it remained unclear whether it is the average blood pressure level or blood pressure variability (BPV) that is responsible for the cognitive decline. In this issue of Circulation, Oishi et al.³ provide new data strengthening the case that BPV is a key driver of the association with subsequent dementia, an effect that may be particularly relevant to AD.

Although blood pressure is often viewed as two simple numerical values, systolic blood pressure (SBP) and diastolic blood pressure (DBP), it is now well-established that both SBP and DBP have marked oscillations in the short-term (24 hours), mid-term (days/weeks) and long-term (years).⁴ Historically, variability in blood pressure was viewed as an impediment towards the accurate assessment of blood pressure recordings and as a phenomenon to be reconciled by improved monitoring; however, over the last twenty years, BPV has been recognized as an independent risk factor for cardiovascular disease.⁴ Recently, several longitudinal studies have reported that increased long-term BPV, independent of the average blood pressure level is associated with a higher risk of cognitive impairment and dementia (Table 1). However, in most studies, BPV was assessed by mid- long-term office measurements, which are subject to considerable bias, and the association between dementia subtypes and BPV assessed by daily measurement in blood pressure at home has not been evaluated.

Table 1. Representative Studies Evaluating BPV and Risk of Dementia or Cognitive Decline.

Reference	Country of origin (N)	BPV measurement	Outcome	Main Results
Nagai et al 20125	Japan (201)	Monthly for 12 months	MMSE and GDS	Higher BPV negatively associated with MMSE scores
Sabayan et al 20136	Europe (5461)	Every 3 months for an average of 3.2 years	Cognitive testing; MRI (hippocampal volume, cortical infarcts)	Higher BPV associated with cognitive decline
Yano et al 20147	USA (2326)	8 visits over 25 years	Cognitive testing	Higher BPV beginning in young adulthood associated with cognitive decline
Alperovitch et al 20148	Europe (6506)	3 visits over 4 years	Dementia according to DSM-IV criteria	Higher BPV associated with development of dementia

Abbreviations: BPV, blood pressure variability; MMSE, Mini-mental status examination; GDS, Global Deterioration Scale; MRI, magnetic resonance imaging; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4^th Edition

Oishi et al.³ report findings from a prospective study of 1,674 Japanese patients who were 60 years or older and without baseline dementia. The study assessed the association between home day-to-day BPV and the risk of incident all-cause dementia, VaD, and AD. All patients measured their blood pressure in the morning for a median of 28 days (range 3-28) using an automated digital electronic blood pressure device. Day-to-day variations in both SBP and DBP were defined using the coefficient of variation (CoV), calculated as standard deviation of the mean blood pressure / (mean blood pressure × 100), and categorized into quartiles. Dementia diagnoses were adjudicated by neurologists or psychiatrists and were based upon rigorous evaluation of clinical information, neuroimaging, or autopsy reports. During the 5-year follow-up period, 194 (11.6%) patients developed all-cause dementia, of which 47 had VaD (2.8%) and 134 had AD (8.0%). The age- and sex-adjusted incidences of all-cause dementia, VaD, and AD increased significantly with increasing CoV quartiles of home SBP (all P-values for trends were <0.05). These associations remained unchanged after adjustment for demographics, risk factors for dementia, and mean SBP values. Compared with patients in the first quartile of CoV levels of home SBP, the risk of developing all-cause dementia, VaD, and AD were significantly higher in those in the fourth quartile for all cause dementia (HR=2.27), for VaD (HR=2.79), and for AD (HR=2.22). Similar associations were observed for CoV levels of home DBP. Although there was no interaction between mean SBP and CoV levels of home SBP, mean home SBP was associated with the risk of VaD, but not with the risks of AD. These results demonstrate a significant association between home day-to-day BPV and the risk of AD and VaD, independent of the average blood pressure level.

Although prior studies have demonstrated an association between cognitive decline and long-term BPV, assessed by monthly or yearly blood pressure measurements in the office, this approach is subject to a number of potential confounders, such as variations of time of the day or season during which BP was measured, differences among blood pressure machines or cuff sizes, changes in anti-hypertensive agents, accumulation of medical comorbidities, and the white coat effect. Given the limitations of long-term blood pressure monitoring, the results of Oishi.³, based on day-to-day monitoring of blood pressure at home, add considerable strength to the association between higher BPV and dementia. Moreover, the majority of prior studies assessing the relationship between BPV and cognitive decline solely focused on patients' MMSE scores and cognitive testing rather than formal diagnoses of dementia.^5-7 Such an approach is hypothesis generating but does not facilitate a mechanistic explanation underpinning the relationship between BPV and specific patterns of neurodegeneration. Previously, Alperovitch et al. found a positive association between BPV and AD but found no such association for VaD.⁸ Oishi et al. is the first study to find an independent association between BPV and both AD and VaD, suggesting that BPV plays an important role in the development of both AD and VaD subtypes. However, an important difference between AD and VaD was found: both higher BPV and higher mean SBP values were associated with VaD, but only higher BPV was associated with AD. These results indicate that, as opposed to the average blood pressure level, BPV may be a more useful indicator for the risk of subsequent AD and may represent a potential target for treatments designed to prevent the development of AD.

What are the potential mechanisms of the deleterious effects of BPV on cognitive function? Brain function is highly dependent on a constant and well-regulated blood supply matched to its dynamic energy needs.⁹ Whereas complete interruption of blood flow leads to irretrievable brain damage, more subtle alterations in the cerebral blood supply, when sustained in time, lead to dysfunction and damage in susceptible brain regions, often associated with cognitive deficits.⁹ The latter may be the case in the effects of BPV on the brain. BPV has been linked with oxidative stress, endothelial injury, impairment of vascular smooth muscle function, and vascular stiffening.¹⁰ Therefore, variations in blood pressure may promote dysregulation of the cerebral vasculature, which in turn, cause a mismatch between the supply of energy substrates and the brain's energy demands. The resulting alterations in the homeostasis of the cerebral microenvironment may lead to brain dysfunction and damage.⁹ In addition, extreme variations in blood pressure may bypass cerebrovascular autoregulation - the ability of the brain to keep cerebral perfusion relatively constant despite changes in blood pressure - and lead to potentially damaging fluctuations in blood flow. Indeed, higher BPV is associated with both macroscopic injury, including stroke, and microvascular injury, including cortical microbleeds and cerebral white-matter hyperintensities.⁴ Interestingly, chronic hypertension may also promote the brain accumulation of amyloid,^{11, 12} a pathological hallmark of AD. In this regard, the novel finding of a lack of association between average blood pressure level increases and AD³, raises the possibility that BPV may be more likely to promote AD pathology. However, data linking specifically amyloid accumulation to BPV is presently lacking.

Certain limitations should be considered. Although short-term BP measurements are subject to less variation than long-term measurements, any time-limited aberration from baseline, such as sickness, medication non-compliance, or inconsistent BP measurement technique may have significantly affected the results of the study. Second, although use of an anti-hypertensive agent was included as a covariate, the authors did not account for the differential effect of certain anti-hypertensive agents on BPV; for example, calcium channel blockers and diuretics appear to have a stronger effect at reducing BPV than do other antihypertensive medications.¹³ Lastly, although no patient had dementia at the time of BPV measurement, it is possible that some patients had pre-existing mild cognitive impairment. Therefore, higher BPV could be the consequence of a pre-existing neurodegenerative process rather than a risk factor for dementia. Indeed, alteration of baroreceptor circuits, which may occur in AD, can result in BPV.¹⁴ However, a factor mitigating this concern is that the results were unchanged after excluding patients with a dementia diagnosis within 2 years of SBP measurement.³

Whether BPV represents a modifiable dementia risk factor is unclear. Data from both the PROGRESS and Syst-Eur trials indicate that reduction in the average blood pressure level is associated with a reduction in dementia.^{2, 11} As BPV was not measured in these trials, it is uncertain whether targeting reduction in BPV, rather than absolute SBP or DBP values, may lead to a further risk reduction in dementia incidence. Furthermore, late life low blood pressure is also associated with dementia,¹⁵ thus raising conflicting advice on how to best treat hypertension in the elderly who have the greatest risk of developing dementia. Nevertheless, the novel findings of Oishi et al.³, in concert with prior work, suggest that BPV, independent of the average SBP or DBP values, may be associated with the development of dementia. If confirmed in a larger cohort, these findings may guide future prospective studies aimed at curtailing the risk of dementia by reducing BPV.