Poor R-wave progression associates with cerebral amyloid deposition: A potential link between heart and brain

Introduction

Brain amyloidosis is one of the key pathological hallmarks of Alzheimer’s disease (AD), which, together with tau neurofibrillary tangles, adversely alters neuronal function and leads to neuronal death.^1,2 The pathogenesis of disease from amyloid accumulation is however not unique to AD, as deposition of amyloid can occur in nearly every organ system throughout the body. For example, cardiac amyloidosis (CA) is the most common cause of restrictive cardiomyopathy in the world^3-5 and is most often attributed to extracellular accumulation of transthyretin (TTR), serum amyloid A, and/or light chain-type amyloid. While multiple genetic factors have been implicated in different types of amyloidosis, increasing age is a unifying risk factor among them.^1,6,7

Moreover, it has been postulated that amyloid-β (Aβ) pathology in AD may itself be associated with cardiac dysfunction, since Aβ deposition has been shown to be present in AD heart specimens.^4,8,9 It is believed that Aβ can enter the systemic circulation via a disrupted blood-brain barrier, a process that allows for the measurement of currently widely-used plasma Aβ biomarkers, depositing within the interstitium and extracellular matrix of cardiac tissue; this can disrupt myocardial architecture and affect cardiomyocyte function, leading to electrical conduction abnormalities on EKG.^4,9,10

As accumulation of amyloid often precedes clinical manifestations of the disease on the order of years to decades, diagnostic imaging serves a pivotal role in the evaluation of amyloidosis ⁷ . Abnormal accumulation of amyloid can be directly imaged using various radiotracers, namely ¹⁸F-florbetapir, ¹⁸F-florbetaben, ¹⁸F-flutemetamol, and ¹⁸F-flutafuranol within the brain, and Technetium-99m-PYP to visualize TTR-amyloid within the heart. ⁶ In the setting of CA, the presence of amyloid may be indirectly inferred using cardiac magnetic resonance imaging (MRI), echocardiography, and electrocardiography (EKG). ⁶ Low QRS-complex voltage is the most specific finding of CA on EKG, although PRWP, bundle branch block, and sinus bradycardia have also been described.^11,12 Beyond amyloid-specific mechanisms, cardiac dysfunction itself, arising from altered myocardial relaxation, microvascular injury, or autonomic imbalance, has been increasingly recognized as a contributor to cognitive decline and neurodegeneration; studies have shown that impaired cardiac output or subclinical left ventricular dysfunction may reduce cerebral perfusion, promoting tau hyperphosphorylation and neurofibrillary tangle formation, even in the absence of overt AD-associated cardiac abnormality.^13,14

As deposition of amyloid can result in AD and secondary cardiac involvement, this intuitively supports the idea that the presence of amyloid in one organ system may increase the risk of developing amyloid in another, due to parallel pathogenesis of these proteinopathies. Given the projected increase in the incidence of both AD and CA throughout the world over the coming decades, combined with a recent increase in investigational and FDA-approved pharmacologic treatments for different types of amyloidosis, it is essential to further explore the complex relationships between different variations of this disease. ³ This study sought to examine the relationship between AD and electrophysiologic evidence of cardiac dysfunction on EKGs in individuals with varying levels of brain amyloidosis on PET. Little has been documented regarding the incidence of AD with a concomitant cardiac abnormality in vivo.

Methods

Poor R-wave progression is associated with brain amyloidosis

PRWP on EKG was significantly associated with increased brain amyloid deposition, as quantified in Centiloids (regression coefficient = 45.2 ± 12.15, 95% confidence interval [21.3, 69.2], p < 0.001) (Figure 1). This association remained statistically significant in subsequent multivariable ordinary least squares regression models. After adjustment for age and sex (Model 1), PRWP was associated with higher amyloid burden (coefficient = 41.5, p < 0.001). Further adjustment for cardiometabolic comorbidities, including hypertension, hyperlipidemia, coronary artery disease, and obesity (Model 2), strengthened the association (coefficient = 138.0, p < 0.001). The association persisted after additional adjustment for APOE ε4 carrier status (Model 3; coefficient = 145.0, p < 0.001). Adding APOE ε2 carrier status did not significantly change the results (coefficient = 143.0, p < 0.001). Across all models, the direction and magnitude of the association were consistent, supporting a robust relationship between PRWP and brain amyloidosis. The other EKG abnormalities of interest were not associated with brain amyloidosis, including low QRS voltage (p = 0.69), bundle branch block (p = 0.23), and sinus bradycardia (p = 0.41).

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Figure 1.

Association between EKG abnormalities and amyloid deposition on PET. Violin plots show Centiloid values in participants with and without EKG evidence of (A) poor R-~>-->wave progression; (B) sinus bradycardia; (C) bundle branch block; and (D) low QRS voltage. White dots indicate the median; dark boxes represent interquartile ranges.

We also performed logistic regression analyses using two different Centiloid thresholds for amyloid positivity. Using the threshold of >11 CL (based on TRAILBLAZER-ALZ 2), PRWP was associated with a higher likelihood of amyloid positivity (OR = 6.06, 95% CI [1.68, 28.47], p = 0.009), which remained significant after adjusting for age and sex (OR = 4.91, 95% CI [1.32, 23.57], p = 0.025). Using a threshold of >18 CL, the association was even more pronounced (OR = 8.24, 95% CI [2.28, 38.88], p = 0.003), and again persisted after adjustment for age and sex (OR = 6.77, 95% CI [1.82, 32.69], p = 0.007).

Poor R-wave progression is weakly associated with cortical tau deposition

PRWP was marginally associated with a higher likelihood of cortical tau deposition on PET (odds ratio = 3.65, 95% confidence interval [1.00, 13.41], p = 0.05) (Figure 2). However, the association weakened after adjusting for age (odds ratio = 3.36, 95% confidence interval [0.91, 12.44], p = 0.069), suggesting that age may partially confound this relationship. In contrast, no significant association was observed between PRWP and tau deposition in the MTL (odds ratio = 2.22, 95% confidence interval [0.57, 8.61], p = 0.25).

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Figure 2.

Forest plot showing the association between specific EKG findings and cortical tau positivity on PET. Each blue square represents the odds ratio (OR) point estimate, with horizontal lines indicating the 95% confidence interval (CI). OR > 1 suggests increased likelihood of tau positivity; OR < 1 suggests decreased likelihood. Log scale used for the odds ratio axis.

Discussion

The study was driven by the hypothesis that amyloid accumulation in the brain in AD may occur in parallel with amyloid accumulation in the heart, leading to subclinical EKG abnormalities. Alternatively, cardiac abnormalities seen on EKG may emerge as a response to brain amyloidosis in AD. Either hypothesis would support the use of EKG as a low-cost, screening tool for AD-associated cardiac dysfunction. Given the rising prevalence of both conditions in our aging population and emerging amyloid-targeting therapies, understanding mechanisms leading to both could allow for early intervention.

Our findings point to an association between PRWP on EKG and greater brain amyloid deposition, providing evidence of early changes in the heart in association with brain amyloidosis. Additionally, both PRWP and sinus bradycardia were associated with a higher likelihood of cortical tau deposition, which suggests that cardiac electrophysiologic abnormalities may reflect or be a response to AD pathology in the brain.^8,27,28 Notably, no significant associations were observed between brain amyloid/tau deposition and other EKG abnormalities, including low QRS voltage and bundle branch block.

The significant association between PRWP and brain amyloid deposition aligns with prior research suggesting a link between cardiac dysfunction, possibly related to amyloid deposition, and AD. For example, Troncone et al. detected Aβ₄₀ and Aβ₄₂ amyloid within the endomyocardium of AD patients using immunoblot and ELISA analysis, while Elia et al. identified Aβ amyloid in the endomyocardium of a mouse model of AD.^4,29 The presence of amyloid within the endomyocardium suggests a direct infiltrative process in which Aβ deposits in the interstitium and extracellular matrix of cardiac tissue, disrupting cardiomyocyte function; specifically, the replacement of myocardium with non-conductive amyloid fibrils in the anterior or septal regions can lead to the loss of R-wave amplitude, manifesting as PRWP on the EKG.^{12,29 30} The systemic circulation of Aβ, likely via a disrupted blood-brain barrier, underscores that AD should perhaps be viewed not as a brain-isolated event, but as a systemic proteinopathy that we can currently monitor with plasma biomarkers and measurable cardiac electrophysiologic consequences.^4,10,29,30 The persistence of the association between PRWP and amyloid deposition after adjustments for age, sex, APOE status, and comorbidities underscores a robust link between this cardiac finding and brain amyloidosis. Furthermore, the association with worse global CDR scores indicates that PRWP may occur with more advanced disease, potentially mediated by amyloid deposition or other cardiac abnormalities.

The associations of PRWP and sinus bradycardia with cortical tau deposition are novel findings that suggest a potential link between cardiac electrophysiologic abnormalities and tau pathology. PRWP showed a marginally significant association with cortical tau deposition, whereas sinus bradycardia was significantly associated with cortical tau deposition. These findings may reflect a shared mechanism involving autonomic nervous system (ANS) dysfunction, as tau accumulation in key regions such as the insula, anterior cingulate, and brainstem is known to disrupt central autonomic control, potentially manifesting as cardiac abnormalities like bradycardia.^31,32 Literature supports this hypothesis, demonstrating that tau pathology in autonomic regulatory regions is associated with reduced heart rate variability (HRV), a marker of ANS dysfunction, in AD patients.^33-3437 Additionally, big tau deposition has recently been shown in the heart, with hyperphosphorylated tau aggregates present in heart specimens of people with heart failure (HF) and AD ³⁸ . Reduced HRV has also been linked to cognitive decline and abnormal amyloid/tau ratios, suggesting a complex interplay between cardiac and neurodegenerative processes. ³⁹ The lack of statistical significance association with MTL tau deposition for both PRWP and sinus bradycardia indicates that these EKG abnormalities may be specifically related to cortical tau pathology, possibly due to the regional distribution of tau in areas critical for autonomic regulation.

Altogether, findings show that autonomic dysfunction driven by cortical and brainstem tau pathology may serve as a primary mechanism underlying the observed EKG abnormalities, rather than direct cardiac amyloid infiltration. Tau accumulation within the insula, anterior cingulate, and medullary autonomic nuclei can impair sympathetic and parasympathetic regulation, producing bradyarrhythmia and conduction changes detectable on EKGs.^34,40,41 This interpretation aligns with evidence linking tau burden in autonomic control centers to heart rate variability reduction and cardiac rhythm instability in AD.

EKG is a rapid, low-cost, and low-risk tool for detecting cardiac abnormalities, making it valuable for identifying early signs of cardiac dysfunction in AD patients. PRWP was included as a primary outcome because it serves as a sensitive, though nonspecific, marker of altered ventricular conduction that can precede the overt restrictive cardiomyopathy seen with cardiac amyloidosis. As Aβ circulates systemically and deposits within the myocardium, it may induce cytotoxicity through apoptosis and intracytoplasmic calcium dysregulation, creating a proarrhythmogenic state.^12,27 The disruption of cardiomyocytes by these Aβ fibrils may impair the transmission of electrical impulses, leading to arrhythmias, such as PRWP and sinus bradycardia.^{12,42,12,42,43} Similarly, mitochondria-mediated toxicity has been also shown to be induced in cardiac cells by Aβ.^27,28 PRWP, as an early and sensitive marker of conduction anomalies, may reflect amyloid infiltration in conduction pathways, while sinus bradycardia may reflect amyloid and/or tau deposition in the sinoatrial node.^12,29 The absence of a significant association with low QRS voltage, despite its historical specificity for CA, may be due to its lower sensitivity, as only approximately 25% of CA patients exhibit this finding, as noted by Martinez-Naharro et al. ⁴⁴ The non-significant associations with bundle branch block (p > 0.05) may also reflect its lower sensitivity to early amyloid deposition or its association with more common, non-AD-related etiologies.

The non-specific nature of PRWP and sinus bradycardia complicates their use as diagnostic markers for AD-associated cardiac abnormality, as these findings can arise from various etiologies. Current nuclear medicine techniques, such as Technetium-99m-PYP imaging, are specific to TTR-type CA and do not detect Aβ₄₀ or Aβ₄₂ amyloid, limiting their utility in this context.^7,12,45 Therefore, alternative diagnostic modalities, such as echocardiography or cardiac MRI, should be considered to evaluate cardiac abnormalities in AD patients with these EKG findings.^45,46 The potential link between cortical tau pathology, ANS dysfunction, and cardiac rhythm abnormalities suggests that EKG could serve as a low-cost, screening tool to identify patients at risk for AD-related pathology, warranting further neuroimaging or cognitive assessment. ⁴⁷

While our study focused on EKG-derived markers, we acknowledge that EKG abnormalities alone cannot establish the presence or mechanism of cardiac involvement in AD and should be viewed as hypothesis-generating. Confirmation with complementary cardiac phenotyping will be critical in future studies. For example, echocardiography and cardiac magnetic resonance imaging can detect myocardial infiltration, wall thickness changes, strain abnormalities, and tissue characterization not captured by EKG, while circulating biomarkers may provide additional insight into cardiomyocyte injury and amyloid-related toxicity.^45,48 Moreover, autonomic metrics such as heart rate variability may offer a quantitative assessment of neurocardiac dysfunction and may help link cortical and brainstem tau pathology with cardiac electrophysiologic changes.^35,36,45,49 Integrating EKG with multimodal cardiac imaging, biomarkers, and autonomic assessments will be essential to clarify mechanisms and guide subsequent studies of AD-associated cardiac dysfunction.^11,50,51

This retrospective analysis has several limitations. First, it focused solely on EKG findings, without incorporating other diagnostic modalities for AD-associated cardiac abnormality as noted, such as serum biomarkers, echocardiography, cardiac MRI, or endomyocardial biopsy. Second, the study was limited to Aβ amyloid and did not evaluate other amyloid variants, such as TTR, serum amyloid A, or light chain amyloid. Third, the analysis did not directly assess ANS dysfunction or HRV, which could mediate the observed associations between EKG abnormalities and cortical tau pathology. Future prospective studies should integrate multimodal imaging, serum biomarkers, and HRV assessments to further elucidate the relationship between cardiac abnormality, AD, and ANS dysfunction. Pathological studies confirming Aβ and tau deposition in cardiac tissue would also strengthen the mechanistic understanding of these associations.