Aortic Stiffness and the Risk of Incident Mild Cognitive Impairment and Dementia

Introduction

The integrity of the body’s largest artery may contribute to disease of the smallest cerebral vessels. The compliant large arteries smooth out pulsations of blood flow ensuring near steady flow through smaller peripheral vessels.¹ With aging, the aorta progressively stiffens and dilates,² which facilitates transfer of pressure and flow pulsatility to peripheral organs.^{1, 3} Small cerebral vessels appear susceptible to high aortic stiffness because the brain is a high flow, low resistance organ meaning that pulsatile flow penetrates deeply into the cerebral vasculature.^1–4 Excessive transmission of pulsatile energy into the microcirculation may cause hypertrophic remodeling and rarefaction of small cerebral vessels, possibly resulting in microvascular ischemia or hemorrhage.⁵

High aortic stiffness has been associated with vascular brain injury including stroke, silent infarcts, white matter injury, cortical atrophy and cognitive decline.^{4, 6–13} The association between aortic stiffness and vascular lesions is important because the accumulation of vascular brain injury is associated with an increased risk of dementia.¹⁴ Aortic stiffness has also been linked with the pathological and clinical hallmarks of Alzheimer’s disease (AD), including amyloid-β aggregation¹⁵ and deficits in episodic memory.¹⁶ Based on these findings, there is a strong rationale to suggest an association between aortic stiffness and the risk of clinical cognitive impairment and incident dementia. Yet, to our knowledge, there is no direct evidence to support this assertion. The aim of the present study was to investigate the association of aortic stiffness with the risks of incident mild cognitive impairment (MCI) and dementia in participants of the Framingham Heart Study (FHS) Offspring cohort.

Methods

The FHS Offspring cohort is a prospective, community-based cohort study conducted in the town of Framingham, Massachusetts, USA. Enrollment commenced in 1971 with the recruitment of 5124 participants. The cohort has been examined 9 times, with the latest examination concluding in 2014. For the present study, we used the 7th examination cycle (1998^–2001) as a baseline, from which we calculated the prospective risk of incident MCI and dementia in adults aged 60 years or older. Applanation tonometry on the study cohort begun after the commencement of the 7^th exam cycle, hence carotid-femoral pulse wave velocity (CFPWV) was not measured on approximately the first third of participants who completed the 7^th exam. There were 3539 participants who attended exam 7, of whom, 1928 participants were aged 60 years or older at exam 7. Of these 1928 participants, 1206 had CFPWV measured. For the analysis of incident dementia, we excluded 13 participants who had prevalent dementia at baseline and 92 participants who had no follow-up for dementia, leaving a sample of 1101 participants. For the analysis of incident MCI, we excluded 30 participants with dementia or MCI at baseline and a further 108 participants who did not have follow-up for MCI, leaving a sample of 1068. All participants provided written informed consent and the study was approved by the Institutional Review Board and Boston University Medical Center.

Results

The sample demographics are displayed in Table 1. Over 10 years of surveillance, we observed 106 (10%) cases of MCI and 77 (7%) cases of dementia, 59 (5%) of which were clinically consistent with AD.

Discussion

This prospective, community-based cohort study confirms an association between aortic stiffness and the development of MCI and incident dementia. Specifically, we report an association between higher aortic stiffness and an increased risk of incident MCI in the whole sample and with an increased risk of incident dementia in non-diabetics. Aortic stiffness was also associated with clinical AD independent of age and sex, although results were no longer significant after adjusting for the APOE ε4 allele and vascular risk factors. Prevalent hypertension was not associated with incident MCI or dementia in our sample.

A large body of previous work has demonstrated associations between high aortic stiffness, vascular brain injury and cognitive decline.^{4, 6–13} However, such work does not explain whether aortic stiffness is simply associated with ‘normal’ brain aging, vascular brain injury due to small vessel disease or the beginnings or a neurodegenerative process leading to clinical dementia. A cross-sectional study reported aortic stiffness to be higher in both MCI and dementia as compared to healthy controls,²⁶ although the temporal association between aortic stiffness and dementia could not be established. To our knowledge, only the Rotterdam study has investigated the prospective association between aortic stiffness and the risk of incident dementia.²⁷ Whereas aortic stiffness was not associated with dementia, and MCI by Petersen criteria was not assessed in the Rotterdam study, the authors did find an association between aortic stiffness and poorer executive function. Other cohort studies have linked aortic stiffness to cognitive decline in the 8th to 10th decades of life.^{10–12, 28} The present study extends this previous work by demonstrating an association between aortic stiffness and the development of clinical MCI, i.e., cognitive impairment beyond that typically expected for age and education, in the absence of clinical dementia.

Although the present study does not establish causality between aortic stiffness and the development of MCI or dementia, there is a strong empirical and mechanistic framework to suggest that this may be the case. Aortic stiffening increases the transmission of pulsatile energy into small cerebral vessels^{1, 3} and numerous studies have associated aortic stiffness with a higher burden of vascular brain injury.^{4, 6–8, 11–13} Meta-analysis of available studies has demonstrated relationships between aortic stiffness and evidence of cerebral small vessel disease including white matter hyperintensities, silent brain infarcts, cerebral microbleeds and cognitive impairment.^{6, 7} Injury to deep white matter may follow from high aortic stiffness given that such tissue is perfused by the short ascending branches arising from the circle of Willis, which are less able to dampen high pressure and flow pulsatility as compared to the tortuous vessels that perfuse the cerebral cortex.²⁹ Aortic stiffening is also related to impaired microvascular reactivity,³⁰ reduced cerebral perfusion,³¹ BP variability³² and incident hypertension,³³ which are also related to vascular brain injury and cognitive impairment.^{34, 35} Recent research showed that white matter hyperintensities and cerebrovascular remodeling explained 41% of the observed association between aortic stiffness and memory function.²⁹ Finally, the arterial pulse wave is also thought to propel the movement of cerebrospinal fluid along perivascular spaces.³⁶ Changes in pulsatile flow dynamics, following from aortic stiffening, may alter this process potentially disrupting the clearance of metabolic waste from the brain.

As dementia involves the irreversible loss of neurons, it is important to find ways to prevent dementia before onset. The characterization of those with MCI has been advocated because such individuals are at an increased risk of dementia and may be ideal candidates for intervention.²³ Importantly, aortic stiffness can be lowered through appropriate pharmacological therapy, dietary change and lifestyle intervention.³⁷ As CFPWV is not routinely used in clinical care, the lowering of aortic stiffness is generally achieved indirectly and incidentally, as a consequence of efforts to lower brachial BP. However, it remains unclear whether lowering aortic stiffness can reduce the risk of developing MCI and dementia. We are unlikely to have an answer to this question in the near future given the difficulties in designing appropriate clinical trials. As with exposure to hypertension, high aortic stiffness likely leads to the insidious accumulation of cerebrovascular injury, with clinical dementia only becoming apparent decades following sustained exposure. It is thus extremely challenging for clinical trials to ascertain whether treating aortic stiffness can lower the risks of MCI and dementia. Nevertheless, reducing vascular risk factors such as aortic stiffness, through healthy lifestyle choices and possible pharmacological treatments, is already encouraged for the purpose of preventing heart disease and stroke.³⁸ Based on the results of numerous cohort studies, the benefits of maintaining normal arterial stiffness may extend to lowering the risk of clinical cognitive impairment and dementia.³⁹

Interactions revealed that aortic stiffness was associated with an increased risk of all-cause dementia, but only in those without diabetes. Individuals with type II diabetes have been shown to be at an increased risk of dementia, although the mechanisms linking diabetes to dementia remain uncertain.⁴⁰ It is possible that those with diabetes are at an increased risk of dementia through largely metabolic rather than hemodynamic mechanisms, stemming from insulin resistance, disrupted insulin signaling and hyperglycemia. As an alternative explanation, those with diabetes and high aortic stiffness may have been at an increased risk of dying from competing illness, prior to dementia onset.

Our study was limited by the observational design, which precludes conclusions on the causal link between aortic stiffness and outcome. Secondly, our sample was comprised mostly of white Caucasians, limiting the applicability of our findings to other ethnic groups. We observed interactions between CFPWV and diabetes status when predicting incident dementia but not MCI and we cannot rule out the possibility of chance associations. CFPWV is not routinely used in clinical practice, perhaps owing to time constraints, the need for specialized equipment and operator training. However, with mounting evidence linking CFPWV to asymptomatic organ damage, cardiovascular disease and chronic kidney disease, the measurement of CFPWV is now advocated by clinical guidelines, with use becoming more widespread both in research and clinical practice.³⁸

We demonstrate that high aortic stiffness, measured as CFPWV, was an independent predictor of incident MCI in the whole sample and of incident dementia in non-diabetics. Limiting aortic stiffening with aging, through healthy lifestyle, diet and possible pharmacological therapy, may thus help protect against later life vascular brain injury and cognitive impairment.