Baroreflex Sensitivity and Long-term Dementia Risk in Older Adults

Abstract

Background:

Increased blood pressure (BP) variability is linked to dementia risk, but the relationship between baroreflex sensitivity (BRS), a fundamental mechanism for maintaining stable BP, and dementia risk is undetermined.

Methods:

We tested the hypothesis that impaired BRS is associated with increased dementia risk in 1,819 older adults (63% women; age: 71.0 ± 6.3 years) from the community-based Rotterdam Study. Cardiac BRS was determined from a 5-minute beat-to-beat BP recording at supine rest between 1997 and 1999. Cardiac BRS measures the correlation between changes in consecutive beat-to-beat SBP and subsequent responses in heartbeat intervals, with a higher value indicating better BRS. The primary outcome was incident dementia ascertained from baseline through January 1, 2020; the secondary outcome was all-cause mortality.

Results:

During a median follow-up of 14.8 years, 421 participants developed dementia. The association of cardiac BRS with dementia risk differed by antihypertensive medication use (P for interaction=0.03) and was only observed in participants not taking antihypertensives. Specifically, in those not taking antihypertensive medication, reduced BRS was associated with a higher risk of dementia (adjusted hazard ratio [HR] comparing bottom versus top quintiles: 1.60; 95% CI: 1.07-2.40, P for trend=0.02). Reduced BRS was also associated with an increased risk of death (corresponding HR: 1.76; 95% CI: 1.32-2.35). The association remained after adjusting for average BP and BP variability.

Conclusions:

Impaired BRS partly explains hypertension-related brain damage and excessive dementia risk beyond conventional BP measures, making it a potential novel biomarker for early detection and prevention of dementia.

Graphical Abstract

Introduction

With increasing life expectancies, Alzheimer’s disease and related dementia, the most common neurodegenerative disease in older adults, pose major public health challenges.^1,2 Vascular factors, and hypertension in particular, are major modifiable risk factors for dementia.^3,4 However, the relationship between late-life blood pressure (BP) and dementia is not completely understood. Data from numerous studies have shown null or even reversed associations between late-life BP levels and dementia risk.^5,6 Additionally, emerging evidence also links abnormal BP dynamics to a higher risk of dementia. Thus far, BP dynamics have been primarily operationalized as increased BP variability and decreased BP complexity.^7–13 However, maintaining stable BP requires elaborate underlying feedback mechanisms involving peripheral sensory neurons, autonomous central processing, and adaptations of sympathovagal balance. The efficacy of these mechanisms can be assessed through cardiac baroreflex sensitivity (BRS), a fundamental buffering mechanism that maintains stable BP by regulating heart rate.¹⁴ Thus, we hypothesized that impaired cardiac BRS is associated with the development of dementia.

Cardiac BRS is suggested to decline with age, potentially due to increased oxidative stress, arterial stiffness, and decreased cardiac cholinergic responsiveness.^14,15 This decline in BRS may contribute to the development of dementia by increasing the occurrence of both hypertensive and hypotensive episodes and BP variability, thereby placing the brain at risk of hypoperfusion, vascular injuries such as cerebral small vessel disease, and its sequelae.^{16, 17} While reduced BRS has been reported to be associated with impaired memory and memory decline,^18,19 its association with incident dementia remains undetermined. Previous studies have shown that BRS predicted mortality independent of other vascular risk factors in patients with myocardial infarction,^20,21 but the relationship between BRS and the risk of death in generally healthy older adults is also undetermined. Furthermore, antihypertensive medications, such as angiotensin II receptor blockers and beta-blockers, have been shown to modulate BRS.^22–25 Nevertheless, it remains unknown whether antihypertensive medication use modified the putative association of BRS with health outcomes. In the current study, we investigated the relationship between cardiac BRS and the subsequent risk of dementia and death in the population-based Rotterdam Study with a follow-up of up to 23 years.

Methods

The data is not available in a public repository due to legal and ethical restraints; however, it can be made available to interested researchers upon request to the data manager Frank J. A. van Rooij (f. vanrooij@erasmusmc.nl) following the cohort policies. The analytical code is available from the corresponding author upon reasonable request.

Study Population

This study is embedded in the Rotterdam Study, an ongoing population-based prospective cohort study in Rotterdam, The Netherlands. The cohort has been described in detail previously.²⁶ Briefly, the study was initiated in 1990 with a study population of 7,983 participants aged ≥55 years, who were living in the Ommoord suburb of Rotterdam. The current study includes a randomly selected subset of 2,531 participants who completed continuous beat-to-beat BP measurements during the third examination round of the Rotterdam Study, conducted between 1997 and 1999. These measurements were used to assess baseline BRS in the current study. Participants with any of the following conditions were excluded from the current study: 1) clinical diagnosis of dementia before and at the third examination (n=60); 2) history of cardiovascular disease reported via interviews and verified by medical records before and at the third examination, including stroke, coronary heart disease (i.e. myocardial infarction, percutaneous coronary intervention, or coronary artery bypass grafting), and atrial fibrillation verified by a 12-lead resting electrocardiogram test (n = 477); and 3) incomplete beat-to-beat BP assessment (≤300 seconds of continuous measurement, n=175). Participants with a prior history of cardiovascular disease were excluded to reduce the confounding effects of vascular comorbidity and related treatments on BRS and its association with dementia. Ultimately, 1,819 eligible participants were included in the current study. The Rotterdam Study has been approved by the institutional review board (Medical Ethics Committee) of the Erasmus Medical Center and by the review board of The Netherlands Ministry of Health, Welfare and Sports, and written informed consent has been obtained from all participants.

Continuous beat-to-beat BP and Baroreflex Sensitivity Assessment

Continuous beat-to-beat finger BP was measured noninvasively using Finapres (TNO BioMedical Instrumentation, Amsterdam, The Netherlands) at the middle finger of the left hand when the participant was supine. The participant rested for at least 5 minutes before the test and was asked to refrain from speaking and movement and maintain normal breathing throughout the assessment. Beat-to-beat BP and inter-beat interval were recorded continuously for at least 5 minutes and were sampled at 100 Hz. Finger BP assessed using Finapres has been validated against brachial BP in previous studies.²⁷ The BeatScope software package (TNO BioMedical Instrumentation, Amsterdam, The Netherlands) was used to inspect and remove waveform artifacts and calculate beat-to-beat systolic BP (SBP), diastolic BP (DBP), and mean arterial pressure (MAP). The first 5-minute stable BP signals were used in the current analyses.

We estimated spontaneous cardiac BRS using the time-domain cross-correlation methods described elsewhere.²⁸ Briefly, we quantified cardiac BRS as the cumulative average of the correlation between changes in consecutive beat-to-beat SBP and subsequent changes in consecutive interbeat intervals that exhibit statistically significant changes in the same direction, with a higher value indicating more sensitive baroreceptor responses. Using a sliding window, a 10-s interbeat interval was cross-correlated with a 10-s interval of SBP measurements, with time shifts between 0 and 5 s, correlating current SBP with later interbeat interval values. The time delay with maximum correlation was chosen, and the BRS for this segment was determined by dividing the standard deviation (SD) of the interbeat interval by the SD of the SBP for that segment. If the correlation is positive and was statistically significant (P<0.05), we recorded the BRS value and the corresponding delay. Each 1-second of the recording is the start of a new computation for the next segments. We computed the mean of all BRS values (in ms/mmHg) obtained from all the individual segments to determine the average BRS for each participant. Additional methodological details on BRS calculation are provided in the supplement (see Supplemental Text and Figure S1).

Dementia and Mortality Ascertainment

The primary outcome is incident all-cause dementia. The secondary cognitive outcome is clinically defined Alzheimer’s dementia, the most common subtype of dementia. Dementia cases were ascertained throughout the study using a standardized protocol.²⁹ All participants were screened for dementia at baseline and subsequent visits using the Mini-Mental State Examination and the Geriatric Mental Schedule.²⁹ Participants having a Mini-Mental State Examination score < 26 or Geriatric Mental State Schedule organic level > 0 underwent further examination and informant interview with the Cambridge Examination for Mental Disorders of the Elderly.²⁹ Participants who were suspected of having dementia underwent extra neuropsychological testing if necessary. In addition, the entire cohort was continuously monitored for dementia through electronic linkage with medical records from general practitioners and the regional institute for outpatient mental healthcare. Available information on cognitive testing and clinical neuroimaging was used when required to diagnose dementia subtype. Based on all the above information, a consensus panel led by a consultant neurologist established the final diagnosis according to standard criteria for dementia (the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised; DSM-III-R). For consistency throughout the study period, Alzheimer’s disease was defined according to the clinical NINCDS-ADRDA-criteria.²⁹ We also assessed all-cause mortality as a secondary outcome. Information on all-cause death for all participants was obtained from the municipal health authorities and the general practitioners in the study area also continuously reported deaths. Participants were followed for their dementia status throughout January 1, 2020. Follow-up was complete for 96.8% of potential person-years.

Other Relevant Variables

Smoking habits, alcohol consumption, medication use, body mass index, total cholesterol, high-density lipoprotein cholesterol, physical activity, depression, and diabetes mellitus were assessed at the third examination (baseline of the current study). Depression was assessed using the Dutch Version Centre for Epidemiological Studies Depression Scale (CESD), with a CESD score of ≥ 16 indicating the presence of depressive symptoms.³⁰ The apolipoprotein E (APOE) genotype was determined using polymerase chain reaction on coded genomic DNA samples. Aortic stiffness was assessed by carotid-femoral pulse wave velocity using an automatic device (Complior Artech Medicla, Pantin, France ) at the third examination.^31,32 Pulse wave velocity (meters per second) was assessed as the ratio of the distance traveled by the pulse wave between the sternal notch and the femoral artery and the delay in pulse transit time.³³ Common carotid artery stiffness was measured by the common carotid distensibility coefficient, derived from vessel wall motion measurements of the right common carotid artery using a duplex scanner at the same visit (Ultramark IV, ATL).³⁴

Statistical Analyses

We first described the distribution of cardiac BRS, stratified by age, office sitting BP, and arterial stiffness indexes mentioned above. We also assessed the correlation between BRS and other beat-to-beat BP dynamic measures, including SBP variability (quantified by the coefficient of variation and standard deviation) and SBP complexity (quantified by sample entropy), as described previously.¹³ In our primary analysis, we assessed the association of cardiac BRS with incident dementia using hazard ratios (HR) estimated from Cox proportional hazards models. Analyses were conducted separately for participants who were and were not receiving antihypertensive medication during the examination, given that antihypertensive medication has been shown to modulate BRS in several randomized trials, ^22–25 and the estimates in the overall sample in the presence of effect modification are not appropriate. The interaction between antihypertensive medication use at the examination and BRS was formally tested on a multiplicative scale by adding a product term to the model. Person-time accrued from the time of beat-to-beat BP measurement (i.e., exposure assessment) until the date of dementia diagnosis, date of death, date of loss to follow-up, or censoring at the end of the study on January 1, 2020, whichever came first. We estimated the cumulative incidence of dementia across quintiles of BRS while accounting for the competing risk of death using Gray’s test for equality.^35,36 As the clinical cut-offs for BRS are not established, we used pre-specified quintile-based categories, with the reference group defined as the highest quintile for BRS. Testing for linear trends across quintiles of BRS was performed by assigning a median value to each group and treating it as a continuous variable. To control for possible confounding, Cox models were built with the adjustment for the following covariates: 1) age, sex in model 1 and 2) additional adjustment for education level (primary, intermediate, higher education), APOE ε4 carrier status, smoking habits (never, past, current), body mass index (<24.9, 25-29.9, ≥30kg/m²), physical activity (total MET [metabolic equivalent of task] hours per week), lipid levels, the presence of depressive symptoms, and history of diabetes in the final model (model 2). The proportional hazard assumptions were tested and verified by including an interaction term with time in the model. Cause-specific HRs were computed to assess the potential etiological relationship in the context of competing risk of death.³⁷ we repeated the above analyses for the clinical diagnosis of Alzheimer’s disease and all-cause mortality as secondary outcomes separately.

In our secondary analyses, to assess potential effect modification in the association of BRS and dementia risk, we also stratified the analyses by age, sex, APOE genotype, and history of diabetes in the subset not taking antihypertensive medication (n=1200). Stratified analyses were not performed for those taking antihypertensive medication due to the small sample size (n=564). Additionally, we assessed the association of BRS with dementia risk after additionally adjusting for mean sitting SBP, SBP variability, SBP complexity, and arterial stiffness all in separate models. We did not adjust for these variables in the primary analyses because they could be mediators or variables in the putative causal chain linking BRS to dementia.

The following sensitivity analyses were performed to test the robustness of the main findings: (1) excluding follow-up within 5 years of BRS assessment to reduce potential reverse causation; (2) censoring participants at the time of incident stroke; and 3) additionally adjusting for baseline cognitive function. Given the different effects of antihypertensive medication on BRS, we further adjusted for types of antihypertensive medications in the subset taking them.

All effect estimates are given with corresponding 95% confidence intervals (CIs). All P values presented are two-sided, and a P value of 0.05 or less was considered statistically significant for all the analyses. Missing covariates (<10% for all covariates) were handled using multiple imputations.³⁸ Statistical analyses were performed using SAS version 9.4 (SAS Institute) and R version 4.1.2 (R Foundation).

Results

Among the 1,819 participants (63% women) with a mean age of 71.0 (6.3) years, 421 participants developed dementia during a median follow-up of 14.8 years (interquartile range 8.8–19.8), including 324 (77.0%) with a clinical diagnosis of Alzheimer’s disease. Table 1 describes the participants’ characteristics. Participants with lower BRS tend to be older, have higher systolic and diastolic BP, a higher prevalence of hypertension and diabetes, and were on antihypertensive treatment. Baseline characteristics comparing participants based on their antihypertensive treatment status are provided in Supplemental Table S1.

Table 1.

Baseline characteristics of the study population

Characteristics*	Overall	Baroreflex sensitivity, quintiles
		Quintile 1	Quintile 2	Quintile 3	Quintile 4	Quintile 5
	(n=1819)	(n=363)	(n=364)	(n=364)	(n=364)	(n=364)
Baroreflex sensitivity, ms/mmHg	7.8 (4.1)	3.4 (0.7)	5.2 (0.5)	7.0 (0.6)	9.1 (0.7)	14.1 (3.5)
Age, years	71.0 (6.3)	72.8 (6.4)	71.5 (6.1)	69.9 (6)	70.2 (6.2)	70.6 (6.5)
Women, %	62.6	68.9	67.3	65.4	60.7	50.5
Systolic blood pressure, mmHg	144 (21)	150 (21)	147 (21)	143 (19)	140 (20)	139 (20)
Diastolic blood pressure, mmHg	76 (11)	78 (12)	77 (11)	77 (11)	75 (10)	75 (11)
History of hypertension, %	66.1	77.1	70.3	64.0	59.7	59.3
Antihypertensive medication use, %	32.0	39.0	29.2	28.8	31.3	31.7
Total cholesterol, mmol/L	5.9 (0.9)	5.9 (1)	6 (1)	6 (1)	6 (0.9)	5.8 (0.9)
HDL cholesterol, mmol/L	1.4 (0.4)	1.4 (0.4)	1.4 (0.4)	1.5 (0.4)	1.4 (0.4)	1.4 (0.4)
APOE4 carrier, %
Yes	26.8	24.5	25.0	26.1	26.6	31.9
No	73.2	75.5	75.0	73.9	73.4	68.1
Education, %
Lower or intermediate education	89.5	91.1	87.6	87.5	92.3	89.0
Higher education	10.5	8.9	12.4	12.5	7.7	11.0
Smoking status, %
Never Smoke	34.4	41.4	37.6	35.9	30.2	26.9
Past Smoker	47.4	42.0	45.6	48.5	48.6	52.2
Current Smoker	18.2	16.6	16.9	15.7	21.2	20.8
Body mass index, kg/m2, %
<24.9	34.0	29.9	33.4	35.0	36.3	35.2
25-29.9	46.5	43.2	48.9	46.8	46.7	47.1
≥30	19.5	26.9	17.7	18.2	17.0	17.7
Total physical activity, MET-h/week	93.6 (45.2)	88.7 (45.0)	92.7 (42.8)	94.9 (43.9)	97.4 (46.3)	94.5 (47.5)
Presence of depressive symptoms, %	6.0	8.3	3.0	7.4	6.3	4.9
History of diabetes, %	11.6	16.0	12.3	9.7	11.4	8.9

^*Data are shown as mean (SD) or percentage.

Cardiac BRS, vascular aging, and BP phenotypes

As shown in Figure 1, BRS generally decreases with age, at least until age 80. There is a gradient decline in BRS with aortic arterial stiffness (defined as higher pulse wave velocity) and carotid arterial stiffness (defined as lower carotid distensibility). Lower BRS correlated with higher sitting SBP levels and modestly with increased beat-to-beat SBP variability (measured by standard deviation), but not with SBP complexity (measured by sample entropy), with similar correlation patterns observed for DBP metrics (Figure S2). These correlation patterns appear to be more pronounced in individuals not on antihypertensive medication compared to those who were (Figures S3–4). Among individuals on antihypertensive medication, BRS values were higher among those taking beta blockers compared to other antihypertensive classes (P < 0.005), with no significant differences observed for ACE inhibitors and calcium channel blockers compared to other classes (Figure S5).

Figure 1.

Baroreflex sensitivity (BRS) according to age, arterial stiffness, and blood pressure measures

Lower cardiac BRS and dementia risk

As shown in Table 2, the association of BRS with all-cause dementia significantly differed between individuals not taking antihypertensive medication and those who were (P for interaction=0.03). Among participants not taking antihypertensive medication, reduced cardiac BRS was associated with a higher risk of dementia, in a dose-response manner, after adjusting for age and sex, APOE genotype, education, total and HDL cholesterol levels, smoking habits, weight status, history of diabetes, total physical activity, and presence of depressive symptoms (hazard ratio [HR] comparing top vs bottom quantile of BRS: 1.60; 95% CI: 1.07 to 2.40, P for trend=0.02). As shown in Figure 2, the incidence rate of all-cause dementia was higher in individuals with lower BRS after accounting for the competing risk of death (P=0.02). A similar association was observed for clinically diagnosed Alzheimer’s disease, the most common subtype (77%) of all diagnosed dementia cases (Table S2). No such associations were observed in participants taking antihypertensive medication (P for trend=0.22; Table 2) and this association essentially remained unchanged after further adjustment for the class of antihypertensive medication use (Table S3).

Table 2.

Association of cardiac baroreflex sensitivity with the risk of all-cause dementia

	Hazard ratios (95% CI) for dementia by quintiles of baroreflex sensitivity
	1st Quintile (lowest BRS)	2nd Quintile	3rd Quintile	4th Quintile	5th Quintile (highest BRS)	P for trend
Participants not on antihypertensive medication (n=1200)*
No. of events/participants	61/213	63/252	60/250	53/244	46/241
Hazard ratio (Model 1)	1.56 (1.06, 2.31)	1.18 (0.80, 1.74)	1.28 (0.87, 1.89)	1.16 (0.78, 1.73)	1 (ref)	0.05
Hazard ratio (Model 2)	1.60 (1.07, 2.40)	1.37 (0.92, 2.04)	1.32 (0.89, 1.96)	1.22 (0.81, 1.84)	1 (ref)	0.02
Participants on antihypertensive medication (n=564)
No. of events/participants	29/136	18/104	25/101	21/111	31/112
Hazard ratio (Model 1)	0.75 (0.45, 1.25)	0.65 (0.36, 1.17)	0.92 (0.54, 1.57)	0.69 (0.40, 1.20)	1 (ref)	0.24
Hazard ratio (Model 2)	0.68 (0.39, 1.19)	0.70 (0.38, 1.27)	0.95 (0.55, 1.65)	0.67 (0.37, 1.18)	1 (ref)	0.22

Model 1 was adjusted for age and sex.

Model 2 was additionally adjusted for APOE genotype, education, total and HDL cholesterol levels, smoking habits, weight status, history of diabetes, total physical activity, and presence of depressive symptoms.

^*P values for the interaction term between antihypertensive medication use and baroreflex sensitivity were 0.03 for both models.

Figure 2.

Cumulative incidence of all-cause dementia across quintiles of BRS among individuals not on antihypertensive medication

Other secondary and sensitivity analyses

Lower BRS was also associated with a significantly higher risk of all-cause death in a dose-response manner in individuals not taking antihypertensive medication in the fully adjusted model (Table 3). The association of reduced cardiac BRS with dementia did not differ significantly when stratified by age, sex, APOE carrier status, and history of diabetes (Table S4). The association did not essentially change in the following analyses: 1) additionally adjusting for SBP, beat-to-beat SBP variability, SBP complexity, and measures of arterial stiffness in separate models; 2) censoring dementia cases within 5 years of BRS assessment; 3) censoring participants at the occurrence of stroke and 4) additionally adjusting for cognitive function at the same visit with BRS assessment (Table S5).

Table 3.

Association of cardiac baroreflex sensitivity with all-cause mortality

	Hazard ratios (95% CI) for mortality by quintiles of baroreflex sensitivity
	1st Quintile	2nd Quintile	3rd Quintile	4th Quintile	5th Quintile	P for trend
Participants not on antihypertensive medication (n=1200)*
No. of events/participants	110/213	111/252	107/250	101/244	98/241
Hazard ratio (Model 1)	1.68 (1.27, 2.22)	1.26 (0.95, 1.66)	1.26 (0.96, 1.66)	1.16 (0.88, 1.54)	1 (ref)	<0.001
Hazard ratio (Model 2)	1.76 (1.32, 2.35)	1.36 (1.02, 1.81)	1.42 (1.07, 1.88)	1.25 (0.93, 1.67)	1 (ref)	<0.001
Participants on antihypertensive medication (n=564)
No. of events/participants	79/136	53/104	47/101	59/111	53/112
Hazard ratio (Model 1)	1.29 (0.90, 1.83)	1.20 (0.82, 1.75)	1.15 (0.77, 1.70)	1.15 (0.79, 1.67)	1 (ref)	0.17
Hazard ratio (Model 2)	1.31 (0.91, 1.88)	1.21 (0.82, 1.80)	1.24 (0.82, 1.86)	1.18 (0.80, 1.73)	1 (ref)	0.15

Model 1 was adjusted for age and sex.

Model 2 was additionally adjusted for APOE genotype, education, total and HDL cholesterol levels, smoking habits, weight status, history of diabetes, total physical activity, and presence of depressive symptoms.

^*P values for the interaction term between antihypertensive medication use and baroreflex sensitivity were 0.35 for Model 1 and 0.16 for Model 2.

Discussion

In this community-based prospective cohort study in older adults, lower cardiac BRS was associated with an elevated long-term risk of developing dementia and death among participants not taking antihypertensive medication. The association remained unchanged after additionally adjusting for average sitting BP level and beat-to-beat BP variability. The associations with dementia and death risk were not observed in those taking antihypertensive medication. Our study suggests that impaired BP regulation, partly captured by reduced cardiac BRS, may represent a novel early biomarker of elevated dementia risk.

Our study provides new data on the relationship between BRS and the subsequent risk of dementia in community-based older adults. This adds to our understanding of the important role of BP regulation in the pathophysiology of dementia beyond conventional BP measurements. Consistent with studies reporting the cross-sectional association of reduced BRS with worse memory and their concurrent declines,^18,19 our study provides further evidence demonstrating the longitudinal relationship between BRS and the long-term risk of dementia. We also observed a consistent association between reduced cardiac BRS and all-cause mortality, extending previous observations that link BRS to mortality in patients with myocardial infarction over two years^20,21 to healthy older adults over two decades. These new data indicate the novel predictive value of BRS for mortality in a broader population of older adults. Interestingly, these associations were only observed in those not on antihypertensive medication, suggesting that antihypertensive medications may reduce sympathetic drive and blunt the association of reduced BRS with increased dementia risk. Indeed, several randomized trials have shown that certain antihypertensive medications may improve BRS and autonomic function in addition to their BP-lowering effects.^22–24 We observed higher BRS in those taking beta-blockers compared to other antihypertensive medication classes, consistent with previous studies demonstrating that beta-blockers increase BRS at rest in hypertensive patients,^24,25,39,40 although this was not observed in other studies.^23,41 It has been suggested that beta-blockers and angiotensin II receptor blockers exhibit greater effectiveness than ACE inhibitors in enhancing BRS.^22–25 Some antihypertensive medications, especially those acting on the renin-angiotensin system, have also been reported to reduce the risk of dementia,^42,43 possibly by preserving cerebral blood flow⁴⁴ or reducing the development of cerebral microangiopathy.⁴⁵ Taken together, these data suggest that the potential pleiotropic effects of certain antihypertensive medications on BRS, in addition to their BP-lowering effects, may confer additional benefits in reducing dementia risk.

Several plausible explanations may link impaired cardiac BRS to dementia. First, impaired BRS response may lead to abnormal BP patterns, including elevated BP, increased BP variability, and more frequent hypotensive episodes.^14,16,24 These abnormal BP features may collectively contribute to cerebral hypoperfusion and cerebrovascular pathologies, ultimately increasing the risk of dementia.^7–13,16,46 Indeed, several reports have linked impaired BRS to impaired white matter integrity⁴⁷ and lower hippocampal perfusion.¹⁷ Second, BRS may also contribute to dementia risk through cardiac rhythm instabilities²⁰ and its direct impact on cerebral blood flow and cerebral autoregulation, thus impairing cerebral vasculature and contributing to dementia beyond BP regulation.⁴⁸ This speculation is supported by increasing evidence linking autonomic dysfunction to cerebral autoregulation in humans.^49–51 On the other hand, given the insidious onset and long prodromal stage of dementia,⁵² brain regions involved in BP regulation (e.g., the brainstem and its connections with the hippocampus and other brain areas^53–55) could be disrupted years before the clinical diagnosis of dementia and thus impaired BRS, and possibly impaired cerebral autoregulation, may manifest as early signs of dementia (i.e., reverse causation).

Our study has several clinical implications. It demonstrates that BRS declines with age, elevated BP, and arterial stiffness, consistent with prior research.⁵⁶ This underscores the importance of adequately controlling BP and its cumulative cardiovascular damage to prevent adverse outcomes, including dementia.^57–60 It also suggests that monitoring baroreceptor function could be particularly relevant in older adults. On the one hand, BRS may capture hypertension-mediated organ damage above and beyond conventional BP measures, potentially serving as a novel early biomarker for predicting dementia risk. On the other hand, modulating BRS could inform tailored therapeutic approaches that might further reduce dementia risk. For example, certain antihypertensive medications that modulate BRS in addition to their BP-lowering effects,^22–25 as well as physical exercise training,⁶¹ may improve BRS in older adults and reduce subsequent dementia risk and related adverse consequences, which warrants further clinical research. The rapid technological advances in developing more portable beat-to-beat BP devices will enable us to assess BRS in real-world settings and its relevance to important BP features such as diurnal BP variation and resistant hypertension to inform its clinical translation potential.

Several limitations of this study should be noted. First, we derived cardiac BRS based on spontaneous variation in BP during supine resting. While this approach represents a simple, noninvasive method with great potential for clinical translation, it might not fully reflect impairment in BRS during daily life activities such as postural changes and active exercise. Therefore, our study may have underestimated the true relationship between vagally-mediated baroreceptor function and the risk of dementia. Spontaneous BRS is also limited in differentiating between causation and correlation of the relationship between variation in BP and variation in heart rate.⁶² Second, BRS was assessed only once at baseline and we were not able to evaluate its change over time and the impact of this on the observed association with dementia. Third, although our analyses were based on prespecified hypotheses and the modulation role of antihypertensive medication in prior literature, the association was only observed in the subgroup not taking antihypertensive medication. Therefore, the results should be viewed as exploratory in nature and warrant future replication. Moreover, given the observational nature of the study, we cannot rule out potential residual confounding in the observed association between impaired baroreflex sensitivity and dementia risk, such as sleep measures and underlying subclinical brain pathologies. Due to the observational nature, our study is also limited in investigating the class effects of antihypertensive medication on BRS and its association with dementia risk. We also lack data to elucidate the mechanisms that may link BRS to dementia. Finally, the study was conducted among predominantly White older participants, its generalizability to other racial or ethnic groups and younger populations may be limited and further investigations in more diverse populations are needed. Nevertheless, our study provides strong evidence showing the association of impaired cardiac BRS with subsequent risk of dementia in healthy older adults up to 23 years and offers new insights into the role of BP regulation in the etiology of dementia. The long follow-up among generally healthy older adults also makes the association more robust to potential reverse-causation bias.

Perspectives

Baroreflex sensitivity, a fundamental mechanism for maintaining stable blood pressure (BP), is associated with the risk of developing dementia among older adults not taking antihypertensive medication over a follow-up of up to 23 years. This association remained significant after additional adjustments for average sitting BP and beat-to-beat BP variability. Baroreflex sensitivity may serve as a novel biomarker and potential therapeutic target for the early detection and prevention of dementia in older adults. Baroreflex sensitivity declines with age, and monitoring baroreceptor function could be of particular clinical relevance in older adults.

Pathophysiological Novelty and Relevance.

What is new?

• Baroreflex sensitivity, a fundamental mechanism for maintaining stable blood pressure (BP), is associated with the risk of developing dementia among older adults not taking antihypertensive medication over a follow-up of up to 23 years.

• This association remained significant after additional adjustments for average sitting BP and beat-to-beat BP variability.

What is relevant?

Impaired baroreflex sensitivity captures the excessive risk of dementia associated with hypertension beyond conventional BP measures.

Clinical/Pathophysiological Implications?

• Baroreflex sensitivity may serve as a novel biomarker and potential therapeutic target for the early detection and prevention of dementia in older adults.

• Baroreflex sensitivity declines with age. Monitoring and modifying baroreceptor function could be of particular clinical relevance in older adults.

Non-standard Abbreviations and Acronyms

APOE

apolipoprotein E

BRS

baroreflex sensitivity

BP

blood pressure

DBP

diastolic blood pressure

SBP

systolic blood pressure