Blood Pressure Variability and the Risk of Dementia: A Nationwide Cohort Study

Worldwide, nearly 35 million people live with dementia and this number is expected to double by 2030 and more than triple by 2050, representing a public health priority.¹ Due to the lack of effective treatments to prevent or reverse the cognitive decline, the search for putative preventive measures to lower its prevalence rate or slow down its progression may represent a reasonable clinical strategy and have important practical implications.² In this respect, vascular risk factors are placed among those considered of greatest interest. Managing these factors offers a feasible method for managing cerebrovascular impairment.²

Along with the traditionally assessed conditions, such as arterial hypertension, diabetes mellitus, dyslipidemia, or arterial fibrillation, visit-to-visit variability in blood pressure (BP) is related to cerebrovascular damage and independent of mean blood pressure.³ In addition, regardless mean blood pressure, higher blood pressure variability (BPV) is associated with increased white matter hyper-intensity lesions on brain MRI,⁴ increased carotid artery intima media thickness,⁵ and early atherosclerosis progression.⁶

Recently, raised BPV has emerged as a novel risk factor for the development and progression of Alzheimer’s dementia, whose hallmarks include brain parenchymal and vascular deposits of amyloid-β peptide (Aβ), neurofibrillary tangles of hyperphosphorylated tau protein, gliosis, and neuronal loss.⁷ Previous studies have suggested that BPV is a risk factor for cognitive decline. Some findings have examined the association of BPV with structural brain damage^4,8,9 and progression of cognitive decline.^2,10,11 These studies assessed BPV using either systolic BP (SBP) or diastolic BP (DBP)^2,4,8–13 and did not investigate combined effects of SBPV and DBPV.^2,4,8–13 However, the association of BPV with incidence of dementia^12,13 and its subtypes¹³ is not well established. These studies were are also limited by having relatively small study populations (N<6506¹²) or by having difficulties in generalizing findings. The latter was due to the specific populations studied, such as an elderly cohort,^9,12,13 thus there were difficulties generalizing the findings to mid-life hypertension.

Therefore, in the present study, we aimed to evaluate the association between visit-to-visit BPV and the incidence of dementia and its subtypes for a nationally representative sample of adults aged 40 or older. We also investigated the additive effect of having both higher systolic and diastolic BPV on dementia.

Because of the confidentiality of the data used for this study and a strict privacy policy from the data holder that the data must be kept among designated research personnel only, the data cannot be provided to others, whether or not the data are made anonymous.

In this large-scale and long-term follow-up study, we confirmed that higher visit-to-visit BPV is associated with the incidence of all-cause dementia, AD and VaD. In addition, in a novel result, we found that having both higher SBPV and DBPV additively increased the risk of dementia and its subtypes in a general population. Derived from subgroup analysis, these associations were independent of various factors, including use of antihypertensive drugs, BP control status, or absolute BP change during follow-up, providing further support for the association of BPV and dementia incidence.

Consistent with our findings, recent studies showed that increased day-to-day¹³ or visit-to-visit¹² BPV, assessed by CV index, was associated with the development of dementia. In addition, to the best of our knowledge, the present study provides the first evidence that having both higher SBPV and DBPV had a greater impact on the development of dementia, compared with having only one of them.

Vascular and degenerative pathways critically interact and contribute to AD pathology.²² While the exact mechanism remains unclear, possible explanations have been suggested.²³ First, marked fluctuations in BP and inconsistent perfusion result in repeated episodes of tissue hypoxia-ischemia. This oligemia can lead to brain amyloidogenesis by enhancing expression and processing of Aβ precursor protein, activating microglia, impairing neuronal protein synthesis, and causing neuronal damage and cellular death. In particular, these changes occur in the most vulnerable areas such as the hippocampi,^24,25 which are among the sites to be affected earlier stage in AD. Second, the damage to endothelial cells and the blood-brain barrier induced by the BP fluctuations and perfusion imbalance can increase the secretion of proinflammatory cytokines and reactive oxygen species and induce microglia overactivation.²⁶ The upregulation of the neuroinflammatory cascade and the reactive gliosis are key moderators of critical events involved in AD pathogenesis, such as misfolding, aggregation, and propagation of Aβ and tau protein.²⁷ Third, visit-to-visit BPV is an upstream determinant of arterial remodeling. Cerebral arterial remodeling can also contribute to the disruption of vascular dynamics involved in perivascular flow and clearance of Aβ.^28,29 Notably, amyloid angiopathy is commonly observed in pathological analysis of AD-affected brains.³⁰

On the contrary, BPV was also associated with the incidence of VaD, which is caused by an altered supply of blood to the brain, typically by a series of strokes. This is not surprising since VaD is generally considered as a manifestation of cardiovascular disease. High fluctuations of BP levels have been independently associated with arterial stiffness.³¹ Increased large artery stiffness provides direct harmful effects on the structure and function of cerebral penetrating arteries.^32,33 BPV could cause a tsunami effect in the cerebral parenchyma leading to cerebral small vessel diseases, including silent infarcts and microbleeds.³⁴ These subclinical vascular damages caused by higher BPV may play a role in developing dementia. Indeed, a meta-analysis of 13 prospective studies suggested that BPV is a predictor of cardiovascular and all-cause mortality and stroke.³⁵ In line with our study, visit-to-visit BPV has been shown to be associated with stroke incidence.^3,36,37

In the present study, excessive fluctuations in BP consistently increased risk of dementia even after various stratifications. This finding may highlight the causal relationship between BPV and development of dementia. Subgroup analyses also demonstrated that high BPV was related to increased risk of dementia in the groups of subjects younger than 65 years, male, without hypertension, and current smokers. Although statistically significant associations between DBPV and the risk of dementia were found, clinically significance of this finding is unclear due to the presence of only small differences.

The clinical implication of our study lies in the fact that amelioration of BPV could be considered a potentially important target in hypertension. Available data suggest that calcium-channel blockers (CCBs) are superior to other therapeutic classes in attenuating long-term BPV.³⁸ For instance, in the Systolic Hypertension Europe (Syst-Eur) trial, CCBs were found to reduce the incidence of dementia more than other antihypertensive drugs,³⁹ and separate studies have shown CCBs to be most effective for reducing BPV among all antihypertensive drug classes.³⁸ These findings suggest that BP-lowering therapy initiated with a CCBs may offer benefits in reducing dementia risk in high-risk groups for dementia. In accordance with current major guidelines for hypertension, CCBs are preferred for the elderly as first-line hypertension treatment.⁴⁰

One strength of our study is the use of visit-to-visit variability and VIM as our primary methods of BPV measurement. Although a number of methods have been proposed for quantifying BPV, visit-to-visit BPV is a useful and easily measurable marker of cardiovascular disease. Also, visit-to-visit BPV assessment is known to be more suitable in assessing long-term BPV than day-to-day measuremetns.⁴¹ Second, VIM is theoretically better than other indices, such as CV and SD, as VIM is not correlated with the mean level of BP. High BP itself is associated with dementia as evidenced by our own data (Table S1) and that of others,^42–44 so the assessment of the impact of BPV should be independent of BP level itself. However, CV was found to be correlated with mean levels in most cohorts.^3,45,46 To determine the prognostic value of variability, VIM may be useful to derive a measure of variability that is uncorrelated with mean levels. Thus, our study has a particular strength in that we used VIM index to describe visit-to-visit BPV, and this enabled us to further support higher BPV as a predictor of dementia development. In addition, the use of CV and SD in our sensitivity analyses revealed similar results, providing further evidence of the robustness of our finding.

There are several limitations of our study. First, while KNHI provided the protocol for BP measurement, it is possible that such a protocol was not accurately followed in the real-world setting. However, such measurement bias will lead to a decreased association, and the actual association between BPV and dementia would be higher if measurements were optimally taken. In addition, different BP devices were used in each center, and this could be a source of extra variability. However, most people received their examinations in the same hospital near their residence, and hospitals wherein health examinations were performed were certified by the KNHIS and subjected to regular quality control including calibration of equipment on a regular basis. Second, discrepancies between the diagnosis of individuals in medical practice and that recorded in claim data may have led to inaccurate analysis. However, under the KNHIS, the specificity of the data is usually high because this degree of specificity is required to fulfill strict insurance criteria. High sensitivity of the data should also be true because dementia can be detected with only clinically meaningful symptoms owing to accessibility to healthcare system. Third, because this study was based on data that were not originally designed for studying dementia, such as the mini mental state examination, we were not able to assess subject baseline cognitive function. This may be partially overcome by conducting subgroup analysis for dementia development to minimize the risk of influence from those other relevant characteristics. Fourth, there is no information on the ECG abnormalities which might have a substantial impact on the development of dementia. Fifth, this was a retrospective study, and the findings should be interpreted accordingly. To minimize the possible effects of reverse causality, subjects with preexisting dementia were excluded. Sensitivity analysis excluding subjects with outcomes occurring in the first 2 years of follow-up also revealed similar results. Last, selection of study subjects based on repeated participation in health examinations might be a source of bias as healthier people with better health behavior and healthcare access are more likely to participate in regular health checkups.

In this nationwide population-based cohort study, we demonstrated that BPV is an independent predictor for developing dementia and its subtypes. A dose-response relationship was noted between higher BPV and dementia incidence. The data were largely consistent in various subgroups. These findings suggest that BPV is an important risk factor, not only in patients with dementia, but also in general populations. Further research is warranted to examine whether reducing variability of blood pressure parameters decreases adverse outcomes.

This study was performed using the database from the National Health Insurance System (NHIS-2018-1-386), and the results do not necessarily represent the opinion of the National Health Insurance Corporation.