Inflammatory Signatures and Biomarkers: The Renal-Vesical Axis in Alzheimer Progression

Article information

Int Neurourol J. 2026;30(1):3-10

Publication date (electronic) : 2026 March 31

doi : https://doi.org/10.5213/inj.2652008.004

Yebeen Kim, Jaewoon Jung, Asifiwe Clarisse Cirunduzi, Seonghyun Yoon, Seokyoung Bang, Seung-Hoon Yang

Department of Medical Biotechnology, College of Life Science and Biotechnology, Dongguk University, Seoul, Korea

Corresponding author: Seung-Hoon Yang Department of Biomedical Engineering, College of Life Science and Biotechnology, Dongguk University, 30 Pildong-ro 1-gil, Jung-gu, Seoul 04620, Korea Email: shyang@dongguk.edu

Received 2026 January 7; Accepted 2026 January 28.

Abstract

INTRODUCTION

Alzheimer disease (AD) is a prototypical neurodegenerative disorder characterized by amyloid-β plaque accumulation, tau protein hyperphosphorylation, and chronic neuroinflammation [1]. Traditionally, AD has been conceptualized as a disorder confined to the central nervous system (CNS) [2]. Increasing evidence, however, indicates that AD is accompanied by systemic inflammatory responses and functional alterations across multiple peripheral organs [3]. In AD, neuroinflammation and immune activation can disrupt blood-brain barrier integrity and promote bidirectional interactions between the CNS and the peripheral circulation, thereby influencing peripheral organ physiology [4].

Clinically, patients with AD frequently exhibit urological abnormalities, including lower urinary tract symptoms, recurrent urinary tract infections, dehydration, and impaired renal function [5]. These manifestations have often been attributed to agerelated changes or chronic comorbidities rather than to coordinated physiological alterations associated with AD progression [6]. Recent studies suggest that such peripheral abnormalities may arise in parallel with neurodegenerative processes and may reflect broader systemic alterations linked to AD [7]. In this context, the bladder and kidney have attracted attention as peripheral organs that appear particularly sensitive to inflammatory and neurogenic signals.

Both the bladder and kidney are under strong autonomic control and respond dynamically to immune and inflammatory stimuli [8]. The bladder can react rapidly to inflammatory stress through urothelial signaling and sensory afferent pathways [9], whereas the kidney is highly susceptible to circulating inflammatory mediators, oxidative stress, and hemodynamic perturbations. Importantly, these organs operate within a shared systemic inflammatory environment and are unlikely to undergo pathological changes in isolation [10]. Instead, bladder and kidney dysfunction may be co-regulated and mutually reinforcing under chronic inflammatory conditions associated with AD. Despite this, bladder and kidney involvement in AD has rarely been examined using an integrated, axis-based framework.

Beyond their biological responsiveness, the bladder and kidney offer practical advantages as peripheral sites for monitoring. Molecular and inflammatory changes in these organs can be evaluated noninvasively through serum and urine analyses [11], providing accessible insights into systemic pathological states. Nevertheless, a comprehensive synthesis of inflammatory responses and biomarker profiles arising from the bladder and kidney in the context of AD remains limited.

In this review, we focus on the bladder-kidney-brain axis in AD and organize current evidence around inflammatory pathways that link central neurodegeneration with peripheral organ responses. We further examine biomarkers associated with functional alterations, cellular stress, and tissue injury in the bladder and kidney, with particular emphasis on shared inflammatory mediators. Through this integrated perspective, we aim to clarify how peripheral organs reflect the systemic nature of AD and to provide a conceptual framework for future investigations into peripheral indicators of disease-associated changes.

SYSTEMIC AND NEUROGENIC INFLAMMATORY CONTEXT IN AD

Systemic inflammation is a well-recognized feature of AD [12] and provides a biological context for peripheral organ involvement. Elevated circulating levels of proinflammatory cytokines, including interleukin (IL)-6, tumor necrosis factor-α (TNF-α), and IL-1β [13], as well as acute-phase proteins such as C-reactive protein [14], have been consistently reported in patients with AD and are associated with cognitive decline and disease severity. These systemic mediators can influence peripheral organs by altering vascular tone, endothelial function, immune cell trafficking, and tissue susceptibility to inflammatory stimuli [15], thereby creating conditions that favor inflammatory activation in the bladder and kidney.

Peripheral immune dysregulation may further reinforce this inflammatory milieu. Circulating monocytes often exhibit a proinflammatory phenotype, and alterations in T-cell subsets suggest impaired immune regulation [16]. These abnormalities can facilitate inflammatory responses in peripheral tissues through endothelial activation and altered immune surveillance. In parallel, systemic inflammatory signals may influence central neural circuits through cytokine-mediated effects at the blood-brain barrier and other immune interfaces, such as the choroid plexus, contributing to autonomic imbalance and altered central control of peripheral organs [17, 18].

Autonomic nervous system dysfunction is increasingly recognized in AD and represents an important link between central pathology and peripheral inflammation [19]. Altered sympathetic and parasympathetic activity has been reported and may affect organ blood flow, epithelial function, and local immune regulation. Sensory afferent pathways may also become hyperexcitable, leading to exaggerated neural responses to peripheral stimuli [20]. These changes may promote neurogenic inflammation, a process in which neural activity induces or amplifies inflammatory responses through neurotransmitters, neuropeptides, and purinergic signaling molecules [21]. In organs under strong neural control, such as the bladder and kidney, systemic immune activation and autonomic dysfunction may jointly create a permissive background for inflammatory responses in the absence of overt structural damage (Fig. 1).

Fig. 1.

Autonomic dysfunction and systemic inflammation link the brain to bladder and kidney pathology in Alzheimer disease (AD). This schematic illustrates how neurodegeneration in AD is associated with peripheral organ inflammation through autonomic nervous system dysfunction and systemic immune dysregulation. AD-related neurodegeneration disrupts autonomic balance and sensory afferent signaling, thereby influencing central neural circuits and altering neural control of peripheral organs. Concurrently, systemic inflammation and immune dysregulation in the circulation are characterized by elevated proinflammatory cytokines (including interleukin-6, tumor necrosis factor-α, and interleukin-1β), acute-phase proteins, proinflammatory monocytes, and altered T-cell subsets. These circulating mediators modulate vascular tone, promote endothelial activation, and facilitate immune cell trafficking, while also affecting the brain through interfaces such as the blood-brain barrier. In this context, the bladder exhibits neurogenic inflammation driven by exaggerated neural responses and hyperexcitable sensory afferents, whereas the kidney shows peripheral inflammatory activation reflecting systemic inflammatory influences.

INFLAMMATORY RESPONSES IN THE BLADDER AND KIDNEY IN AD

In patients with AD, the bladder exhibits inflammatory responses associated with altered CNS-mediated neural regulation. Disruption of autonomic and sensory nerve function can impair normal micturition reflexes, resulting in sustained urothelial stress [22]. Under these conditions, localized inflammatory responses may persist within bladder tissue, manifesting as a functional inflammatory state driven by neural dysregulation rather than by infection or overt structural damage. Accordingly, bladder inflammation may represent a pathophysiological feature closely linked to the urinary dysfunction frequently observed in patients with AD. These functional inflammatory responses are likely accompanied by local release of inflammatory mediators, including cytokines and chemokines, which may contribute to the persistence of urothelial dysfunction under conditions of ongoing neural dysregulation.

In parallel, the kidney may develop inflammatory responses in reaction to systemic changes associated with AD. Neuro-hemodynamic dysregulation and a proinflammatory systemic environment accompanying CNS pathology [23] can disrupt renal microenvironmental homeostasis, particularly by promoting inflammation within the tubular compartment [24]. Such inflammation may be detectable even in the absence of evident structural injury and may evolve through the gradual accumulation of functional disturbances [25]. Accordingly, the kidney may function not merely as a coincidental site of injury but as a critical peripheral target that reflects disease-associated systemic inflammatory alterations in AD. These tubule-centered inflammatory responses are closely associated with cytokine- and chemokine-mediated shifts in the renal microenvironment.

In this context, inflammatory responses in the bladder and kidney should not be interpreted as independent, organ-confined phenomena. Rather, they are more appropriately viewed as parallel peripheral manifestations associated with dysfunction of the bladder-kidney-brain axis. Within this axis, CNS pathology disrupts neural regulation and inflammatory signaling, including cytokine- and chemokine-mediated pathways, leading to neurogenic inflammation and functional impairment in the bladder alongside tubule-centered inflammatory responses and microenvironmental disturbance in the kidney (Fig. 2).

Fig. 2.

The bladder-kidney-brain axis and peripheral inflammatory dysfunction in Alzheimer disease (AD). This schematic illustrates a conceptual model of the bladder-kidney-brain axis in AD, highlighting how central neuroinflammation is associated with peripheral organ dysfunction. AD-related neuroinflammation, characterized by microglial activation and astrocytic overactivation, contributes to neural dysfunction and altered signaling across the blood-brain barrier (BBB). These central changes are accompanied by systemic inflammation, providing a proinflammatory milieu that affects peripheral organs. In the bladder, autonomic and sensory nerve dysfunction disrupts neural regulation of the urothelium, leading to urothelial stress and functional inflammatory changes associated with local accumulation of proinflammatory cytokines and chemokines. In parallel, the kidney exhibits neurohemodynamic dysregulation and inflammatory alterations within the renal tubular epithelium, reflecting cytokine- and chemokine-associated microenvironmental disturbance. Together, these processes illustrate parallel peripheral manifestations of AD-associated central pathology, in which neural dysregulation and systemic inflammatory signaling converge to influence bladder and kidney epithelial function within the bladder-kidney-brain axis.

INFLAMMATORY BIOMARKERS IN THE BLADDER AND KIDNEY RELATED TO AD

Bladder Biomarkers in AD

Urothelial barrier proteins are essential for maintaining epithelial integrity and regulating interactions between the urinary lumen and underlying tissue. Uroplakin III [26], E-cadherin, and zonula occludens-1 (ZO-1) [27] are key structural components of the urothelium. Alterations in these proteins have been reported under inflammatory and neurogenic conditions and may reflect increased epithelial vulnerability and barrier dysfunction. In the context of AD, such changes are consistent with sustained functional stress on the bladder associated with impaired neural regulation rather than with primary structural injury.

Proinflammatory cytokines and chemokines constitute the dominant biomarker group associated with bladder involvement. Interferon-inducible chemokines, including C-X-C motif chemokine ligand (CXCL)9, CXCL10, and CXCL11 [28, 29], contribute to immune cell recruitment and amplification of inflammatory signaling within the bladder microenvironment. Their detection is consistent with activation of immune-related pathways under chronic inflammatory conditions. Additional proinflammatory mediators, including IL-6, IL-8 [28, 30], TNF-α [28], and monocyte chemoattractant protein-1 (MCP-1/CCL2) [31], have been consistently reported in inflammatory bladder disorders. These mediators indicate local immune activation and sustained inflammatory burden rather than infection or overt tissue damage. In AD, detection of these mediators in urine supports the concept of a functional inflammatory state associated with altered neural control of the bladder.

Growth factors can reflect neuroimmune interactions within the bladder. Nerve growth factor (NGF) [32] plays a central role in sensory nerve sensitization and modulation of inflammatory responses. Altered NGF levels have been associated with bladder dysfunction in inflammatory and neurogenic conditions, consistent with enhanced afferent signaling and neurogenic inflammation. In AD, NGF-related changes are consistent with bladder instability associated with chronic neuroinflammatory and autonomic disturbances (Table 1).

Table 1.

Inflammatory biomarkers associated with bladder and kidney dysfunction in Alzheimer disease

CONCLUSIONS

AD should no longer be regarded as a disorder confined to the CNS but rather as a condition accompanied by coordinated inflammatory and functional alterations in peripheral organs, including the bladder and kidney [45]. Accumulating evidence indicates that neuroinflammation and systemic immune activation associated with AD disrupt autonomic regulation and inflammatory signaling, thereby affecting urological organs that are highly sensitive to neural and inflammatory perturbations.

In this context, the bladder-kidney-brain axis provides a conceptual framework for understanding how CNS pathology is associated with parallel peripheral inflammatory responses. Neurogenic inflammation and functional stress in the bladder coexist with tubule-centered inflammatory activation and microenvironmental disturbance in the kidney, suggesting that these organs reflect shared disease-associated inflammatory pressure rather than independent organ-specific pathology.

Importantly, the bladder and kidney offer practical advantages as peripheral targets for biomarker assessment, because inflammatory mediators and chemokines can be detected noninvasively in urine and serum [46]. Among these, shared biomarkers such as CXCL9 and MCP-1 highlight convergent immune activation across both organs and may reflect early systemic inflammatory changes associated with AD progression, even in the absence of overt urological disease [47-49].

Together, these observations underscore the relevance of urological organs as peripheral indicators of disease-associated inflammatory states in AD. Integrating bladder and kidney biomarkers within the bladder-kidney-brain axis framework may facilitate a more comprehensive understanding of systemic disease involvement and support future efforts to capture early inflammatory alterations associated with AD.

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