Modulating heart rate oscillation affects plasma amyloid beta and tau levels in younger and older adults

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Modulating heart rate oscillation affects plasma amyloid beta and tau levels in younger and older adults

• Jungwon Min,
• Jeremy Rouanet,
• Alessandra Cadete Martini,
• Kaoru Nashiro,
• Hyun Joo Yoo,
• Shai Porat,
• Christine Cho,
• Junxiang Wan,
• Steve W. Cole,
• Elizabeth Head,
• Daniel A. Nation,
• Julian F. Thayer &
• Mara Mather 

Scientific Reports volume 13, Article number: 3967 (2023) Cite this article

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Abstract

Slow paced breathing via heart rate variability (HRV) biofeedback stimulates vagus-nerve pathways that counter noradrenergic stress and arousal pathways that can influence production and clearance of Alzheimer's disease (AD)-related proteins. Thus, we examined whether HRV biofeedback intervention affects plasma Αβ40, Αβ42, total tau (tTau), and phosphorylated tau-181 (pTau-181) levels. We randomized healthy adults (N = 108) to use slow-paced breathing with HRV biofeedback to increase heart rate oscillations (Osc+) or to use personalized strategies with HRV biofeedback to decrease heart rate oscillations (Osc−). They practiced 20–40 min daily. Four weeks of practicing the Osc+ and Osc− conditions produced large effect size differences in change in plasma Aβ40 and Aβ42 levels. The Osc+ condition decreased plasma Αβ while the Osc− condition increased Αβ. Decreases in Αβ were associated with decreases in gene transcription indicators of β-adrenergic signaling, linking effects to the noradrenergic system. There were also opposing effects of the Osc+ and Osc− interventions on tTau for younger adults and pTau-181 for older adults. These results provide novel data supporting a causal role of autonomic activity in modulating plasma AD-related biomarkers.

Trial registration: NCT03458910 (ClinicalTrials.gov); first posted on 03/08/2018.

Introduction

Alzheimer’s disease (AD) incidence rates increase exponentially with age¹. Why does aging increase AD risk so much? One potentially critical factor has been given little attention. During aging, the balance between the sympathetic and parasympathetic branches of the autonomic nervous system shifts^2,3. As people get older, parasympathetic activity declines, as indicated by decreases in heart rate variability (HRV)². At the same time, sympathetic (or noradrenergic) activity increases, as indicated by increases in sympathetic nerve activity and circulating noradrenaline levels⁴. Age-related increases in noradrenergic activity and decreases in parasympathetic activity are associated with AD-related conditions including sleep disorders, diabetes, and heart disease⁵.

Age-related increases in noradrenergic activity along with decreases in parasympathetic activity might influence levels of amyloid-β (Aβ) peptides in the brain and body⁶. Generally, increasing neuronal or cellular activity stimulates release of Aβ⁷. Rodent AD models indicate that noradrenergic agonists/antagonists affect Aβ accumulation and amyloid plaque formation^8,9 and suggest that stressful situations tend to stimulate Aβ peptide release into the interstitial fluid¹⁰. While these findings suggest that countering noradrenergic activity could help decrease Aβ release in the brain, predictions involving tau proteins are not straightforward. Similar to Aβ, neuronal activity increases tau release^11,11,13 and repeated stress induces tau phosphorylation¹⁴. However, research indicates that anesthetics that lower noradrenergic activity induce tau phosphorylation^15,16, and dexmedetomidine, an ⍺2 adrenergic receptor agonist that produces a sedative state, also increases tau phosphorylation¹⁷. In addition, animal studies suggest that arousal states affect brain waste clearance by modulating effectiveness of glymphatic pathways which transport cerebrospinal fluid (CSF) and flush interstitial waste from the brain to veins^18,19. Glymphatic transport was increased when inducing anesthesia with dexmedetomidine, suppressing noradrenaline release²⁰ and when administering adrenergic antagonists¹⁹. Furthermore, stimulating the vagus nerve, which provides parasympathetic innervation, increased CSF penetrance in the brain²¹. Similar dynamics may exist in human brains^22,23. Certainly, sleep affects Aβ levels. One night of sleep disruption increased Aβ concentrations in the CSF^24,25, and older adults with lower slow-wave activity during sleep had higher Aβ and tau accumulation measured by positron emission tomography (PET) scans²⁶. However, the effects of sleep or sleep deprivation may be more related to production than clearance. For instance, measuring Aβ stable isotope labeling kinetics suggest that sleep deprivation increases Aβ production²⁷. Together, these studies suggest that enhancing parasympathetic activity either via improving sleep or directly stimulating the vagus nerve has the potential to reduce Aβ and tau levels.

The vagus nerve can be non-invasively stimulated by breathing around the baroreflex frequency (0.1 Hz or 10 s/breath)²⁸. The 10 s-paced breathing can stimulate brain mechanisms that help control blood pressure and heart beats and boost the amplitude of cardiovascular oscillations²⁹. We hypothesized that, by attenuating noradrenergic activity and enhancing parasympathetic activity, the amplified oscillations could reduce Aβ release and facilitate clearing the aggregation-prone Aβ42 and pTau-181 from the brain to the periphery. To test these possibilities, we added measures of plasma Aβ and tau to a clinical trial involving daily sessions of HRV biofeedback (ClinicalTrials.gov NCT03458910; primary study outcomes were focused on effects on emotion-related brain networks)³⁰. As outcomes that would reflect changes in cellular release of Aβ, we examined plasma Aβ40 and Aβ42 levels. We also included plasma total tau (tTau) and phosphorylated tau (pTau-181) to measure effects on tau proteins. As outcomes that would reflect changes in clearance from the brain to blood, we examined two plasma ratios: Aβ42 to Aβ40 and pTau-181 to tTau. We selected these as clearance-related outcomes as these ratios each involve one plasma biomarker that is more likely to be brain-derived (Aβ42, pTau-181) and one that relates more to peripheral production or release (Aβ40, tTau). Compared with Aβ40, Aβ42 is relatively more prevalent in the brain than in the periphery³¹. Platelets are the major source of peripheral Aβ^7,32 and produce predominantly Aβ40 over Aβ42^7,31. Plasma Aβ42 is more likely than plasma Aβ40 to reflect brain-derived Aβ, as reflected in the stronger correlation between plasma and CSF Aβ42 than between plasma and CSF Aβ40^33,34. Plasma pTau-181 and tTau show a similar brain vs. periphery dichotomy. Once diagnostic groups are controlled for, plasma tTau and CSF tTau do not significantly correlate with each other, and are correlated with different aspects of brain atrophy and cognition^33,35,36,37. In contrast, plasma pTau-181 levels correlate with CSF pTau-181 levels^38,39, suggesting plasma pTau-181 is more likely than plasma tTau to originate in the brain.

To test whether the HRV biofeedback intervention could affect Aβ and tau dynamics, we conducted assays of plasma samples from 108 healthy adults (54 younger and 54 older adults) who were randomized into one of two groups with opposing goals: reducing or increasing the amplitude of heart rate oscillations (Osc− vs. Osc+ condition). In addition to testing effects across age groups, we conducted follow-up analyses separately for younger and older adults. To our knowledge, no prior studies have compared the effects of any interventions across younger vs. older adults on AD biomarkers. However, analyzing the data separately for the two age groups could provide important insights regarding which effects are general across adulthood and which are specific to one age group. In addition, we ran two exploratory analyses. First, to test whether intervention effects on plasma biomarkers were related to changes in noradrenergic activity, in the younger subgroup of the participants (N = 54), we conducted gene expression analyses of circulating blood cells to assess longer-term tonic levels of noradrenergic activity. We used cAMP-responsive element binding protein (CREB)-regulated gene expression as a slow-moving index of β-adrenergic signaling that reflects adrenergic-related transcription activity⁴⁰. Second, we examined the possible association between change in Aβ42/40 ratios and negative emotion as studies indicated that plasma Aβ42/40 ratios are correlated with later-life major depression^41,42.

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