A peripheral perspective on brain health: vascular and skeletal muscle contributions

Abstract

Age- and disease-related declines in brain health contribute to impairments in physical function, yet effective approaches to lessen these declines remain limited. Overall health is governed by a network of interdependent organ systems, such that dysfunction in one system can propagate across others. Although the brain has been viewed as a top-down regulator of vital functions, evidence indicates that cognition is affected by signals from peripheral organs. This interorgan communication likely explains the coexistence of Alzheimer’s disease and related dementias with cardiovascular and metabolic disorders characterized by overlapping pathophysiology. Skeletal muscle and the peripheral vasculature are key contributors to this and represent modifiable systems that can alter brain structure and function. Skeletal muscle regulates myokine release through motor neuron function, contractile activity, and metabolic perturbations, thereby influencing neuroplasticity, mitochondrial function, and inflammatory signaling, and may affect measures of peripheral vascular function, like reactive hyperemia. Other properties of the vasculature, including arterial stiffness, directly affect cerebral perfusion and blood-brain barrier permeability. These systems form a muscle–vascular–brain axis that contributes to brain health and impacts the risk of cognitive impairment. Therefore, our aim was to synthesize the current understanding of interactions among skeletal muscle, the peripheral vasculature, and the brain, and their collective role in maintaining cognitive health. We also highlight recent clinical trials and emerging strategies affecting interorgan crosstalk. These conclusions support a model in which lifestyle interventions targeting peripheral systems, such as resistance training, may preserve brain health across all populations, offering scalable approaches applicable across the lifespan.

Introduction

The growing prevalence of cognitive impairment and neurodegenerative disease has elevated brain health to a major public health priority (1-5), and projections suggest that more than 80 million Americans may be affected by 2050, reflecting a dramatic rise in Alzheimer’s Disease and related dementias (ADRDs) (5). Age remains the strongest non-modifiable risk factor for ADRDs, with additional contributions from genetic susceptibility, especially apolipoprotein E ε4 (APOE-ε4) carriage. Alternatively, there are several modifiable factors like physical inactivity, poor diet, and cardiometabolic dysfunction (e.g., diabetes) that substantially influence disease risk and progression (4, 5). Among ADRDs, Alzheimer’s Disease (AD) is the most diagnosed dementia subtype, but to be clear, vascular abnormalities are present in most individuals with suspected dementia and frequently coexist with hallmarks of AD. It was previously reported in the Religious Orders Study and Rush Memory and Aging Project cohorts that ~87% of participants with probable AD also exhibited abnormal vascular characteristics, alongside additional neurodegenerative pathologies (1, 6). These findings, in conjunction with others, have led to research focused on vascular contributions to cognitive impairment and dementia (VCID) and on the mechanisms by which vascular dysfunction (e.g., endothelial dysfunction, arterial stiffness, and impaired cerebral perfusion) may be a modifiable factor in later-life cognitive decline (1, 2, 6-9).

Within this clinical continuum, mild cognitive impairment (MCI) is recognized as an intermediate clinical stage between normal aging and dementia, and while MCI is associated with elevated risk for ADRDs, the outcomes are heterogeneous, such that it may remain stable or perhaps even revert to cognitively normal (10). Despite advances in detection and treatment, current pharmacological therapies, at best, slow disease progression rather than prevent or reverse pathology or cognitive decline (11). This constraint has substantially contributed to the growing interest in multidimensional approaches targeting modifiable risk factors with the goal of preventing disease onset or delaying progression, rather than reversing established pathology, as demonstrated by large-scale trials like the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) and the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) (12, 13). These approaches emphasize a developing hypothesis that brain health is not exclusively determined within the central nervous system (CNS) but is markedly influenced by interactions with peripheral organ systems.

Interorgan communication has developed into a key determinant of both cardiovascular and neurological health (14-18). The brain, while representing only ~2% of total body mass, accounts for ~20% of whole-body oxygen consumption, showing its reliance on tightly regulated perfusion and metabolic support. Importantly, while cerebral perfusion is tightly regulated by intrinsic processes (e.g., neurovascular coupling, autoregulation, carbon dioxide reactivity), it may also be shaped by peripheral vascular function and metabolic signals, some of which originate in skeletal muscle.

Skeletal muscle functions as an endocrine and metabolic organ by releasing myokines, extracellular vesicles (EV), and mitochondrial-derived peptides (MDP) that exert effects on distant tissues, including the brain (14-18). Extracellular vesicles are membrane-bound vesicles released by cells that selectively package proteins, lipids, metabolites, and nucleic acids (e.g., microRNAs [miRNA]) to mediate interorgan communication. Further, MDPs are small bioactive peptides encoded within the mitochondrial DNA that participate in signaling and help regulate metabolic homeostasis, cellular stress responses, and exercise-induced adaptations. Other exercise-induced factors such as brain-derived neurotrophic factor (BDNF), irisin, and cathepsin B have been implicated in promoting neurogenesis, synaptic plasticity, and angiogenesis (14, 18-20). Many of these factors act through and influence the peripheral vasculature, including endothelial function, arterial stiffness, and microvascular resistance, potentially via nitric oxide (NO) signaling, all of which affect cerebral hemodynamics and blood–brain barrier (BBB) integrity (21-27). Accordingly, the peripheral vasculature not only regulates tissue perfusion but also provides the physical and functional infrastructure through which endocrine, metabolic, inflammatory, and exercise-induced signals are distributed between organ systems, ultimately influencing brain structure and function (Figure 1) (28, 29). Emerging clinical and epidemiological evidence supports the relevance of this muscle–vascular–brain axis, as declines in skeletal muscle strength and endurance, neuromuscular junction (NMJ) integrity (including the motor neuron), and vascular function often precede overt cognitive impairment, which highlights their potential utility as early indicators of risk of neurological decline (30-36). For example, markers of peripheral neuromuscular dysfunction, such as impaired nerve conduction, have been associated with deficits in memory and executive function (34, 37). Similarly, increased arterial stiffness and altered pulsatile hemodynamics are known to impair microvascular function and transmit damaging forces to the cerebrovascular system, leading to BBB dysfunction and impaired neurovascular coupling (23, 38-41). It is also frequently observed that these peripheral impairments coexist and interact synergistically to accelerate cognitive decline (30, 42, 43).

Figure 1.

This model outlines the role of the muscle–vascular–brain axis in regulating brain health. Skeletal muscle, the peripheral vasculature, and the brain engage in bidirectional communication that collectively affect brain function and resilience. Skeletal muscle contributes metabolic, endocrine, and exercise-induced signals that are distributed through the peripheral vasculature, which serves as a systemic integrator by regulating endothelial function, arterial stiffness, microvascular perfusion, and shear stress–dependent signaling. Through its influence on oxygen delivery, hemodynamics, and neurovascular coupling, the vasculature links peripheral tissue health to cerebral blood flow, neuronal metabolism, and cognitive outcomes. Aging, cardiovascular disease, and physical inactivity disrupt this interorgan communication, whereas exercise and other nonpharmacological interventions may restore functional connectivity across the muscle–vascular–brain axis. Created in BioRender. Keller, J. (2026) https://BioRender.com/znjwnzj

In contrast to traditional CNS-focused measures (e.g., neuroimaging), which often carry financial burdens and are ordered at later disease stages, peripheral biomarkers and assessments offer accessible, noninvasive, and potentially prognostic alternatives. Measures of vascular health, including but not limited to pulse wave velocity, and skeletal muscle functional characteristics (e.g., strength, power, and endurance) are highly responsive to interventions and may even provide earlier insight into disease risk (23, 33, 38, 40, 44-48). These previous data strongly support the use of measures of peripheral function not only as possible indicators of brain health but also as viable targets for a wide range of interventions. Indeed, a growing body of research supports the potential of nonpharmacological strategies to positively elicit interorgan communication and enhance brain outcomes. Interventions such as structured exercise, dietary modification, creatine supplementation, passive heating, and remote ischemic conditioning (RIPC) are notable possibilities, as they have previously demonstrated beneficial effects on vascular function, skeletal muscle physiology, and cerebral perfusion (49-53). The mechanisms underlying these adaptations include improved mitochondrial function, reduced inflammation, and augmented endothelial responses, all of which can ultimately support cognitive function. Furthermore, such interventions are consistent with the goal of prevention, underlining the intent to preserve function, delay disease onset, and/or slow disease progression, rather than to reverse advanced pathology. Although exercise remains beneficial even into late adulthood and in individuals with cognitive impairment (54), evidence suggests that establishing a healthy lifestyle earlier in life and maintaining it across the lifespan may build brain and cognitive reserve, thereby increasing resilience to age- and disease-related cognitive decline (55). Longitudinal studies demonstrate that physical activity during adolescence and early adulthood is associated with better cognitive function decades later in life (55), together with emerging evidence that brain aging follows a nonlinear trajectory with acceleration during midlife (50–64 years) (56), support the concept that this phase may be one of the last windows of opportunity to garner meaningful benefits from various interventions (56, 57). These reports help support the view that preserving peripheral health throughout the lifespan, perhaps through exercise and other nonpharmacological interventions, is a proactive approach to limiting cognitive decline. Accordingly, peripheral systems should be viewed as active contributors to brain health rather than merely as mirrors of CNS function. Aging, physical inactivity, and cardiovascular disease (CVD) can disrupt this network, whereas focused interventions may restore healthy interorgan communication across systems.

Therefore, this review aimed to synthesize current understanding of interactions and communication among skeletal muscle, the peripheral vasculature, and the brain, and their collective role in influencing cognitive health. We also highlighted recently reported clinical trials and emerging therapeutic approaches targeting interorgan crosstalk, including nonpharmacological interventions. Readers are also encouraged to consider recent complementary reviews for additional detail and depth (21, 30, 58).

Peripheral vasculature influences brain structure and function

1. Microvascular Function

Increasing evidence supports the peripheral microvasculature as a key determinant of overall health, with dysfunction linked to adverse cardiovascular outcomes, neurodegeneration, and all-cause mortality (38, 47, 59-64). Here, we define the peripheral microvasculature as the small resistance and exchange vessels outside the brain that regulate tissue perfusion and metabolic exchange. Although the mechanistic links between peripheral microvascular function and brain health remain incompletely defined (64), vascular dysfunction is widely recognized as a major contributor to cognitive decline, as reflected in the study of VCID (1-3, 7, 9, 65). Importantly, many risk factors underlying VCID are modifiable (2, 7, 9), highlighting the potential clinical relevance of peripheral vascular assessments. Resistance training may represent an underappreciated intervention, in part because it preserves skeletal muscle mass/function and improves cardiometabolic health (e.g., glucose control)—both key regulators of peripheral microvascular function (7, 66).

The rationale for focusing on peripheral measures includes the similar regulatory mechanisms across vascular beds, such as endothelial-dependent vasodilation, metabolic control of blood flow, and myogenic autoregulation (67). That is, impairments in peripheral microvascular function (e.g., reduced vasodilation in response to stimuli) may denote broader vascular dysregulation rather than isolated limb-specific abnormalities, potentially paralleling dysfunction within the cerebral microvasculature. Peripheral microvascular function is commonly assessed using reactive hyperemia, the transient increase in blood flow following a brief ischemic stimulus, which reflects integrated endothelial, metabolic, and smooth muscle responses (68, 69). This response can be quantified using techniques such as near-infrared spectroscopy (NIRS), venous occlusion plethysmography, and peripheral arterial tonometry (PAT), providing accessible and noninvasive indices of microvascular health (68). These approaches enable the investigation of relationships between peripheral vascular function and indices of brain structure, cerebral hemodynamics, and cognition (38, 47, 61, 64, 70, 71).

Indeed, several studies support a link between peripheral microvascular function and cognitive health. Investigators at the Reynolds Oklahoma Center on Aging reported that a composite vascular health index incorporating multiple peripheral measures was significantly associated with cognitive impairment (r = −0.46) (47). These authors also reported that endothelial function in the skin microvasculature was strongly related to neurovascular coupling (r = 0.9) assessed via functional NIRS during cognitive testing, suggesting that peripheral vascular health reflects cerebrovascular function (61). Similarly, in a cohort of more than 150 adults, reactive hyperemia assessed using PAT was independently associated with MCI, mediating approximately 19% of the relationship between vascular risk and cognitive status (64). Of note, each unit decrease in reactive hyperemia was associated with nearly a twofold increase in the odds of MCI, showing its potential clinical relevance.

Additional evidence suggests that peripheral microvascular function may reflect structural brain integrity. Reactive hyperemia has been positively associated with fractional anisotropy, a marker of white matter integrity, and both measures have been independently related to executive function (60). Consistent with this, we have observed that skeletal muscle oxygen saturation during reactive hyperemia (StO_2max) is associated with processing speed and moderates the relation between age-related aortic stiffness and cognition (38). These data suggest that microvascular function may influence how upstream macrovascular changes affect cognitive aging. This is likely mediated by shared pathophysiological processes, including reduced NO bioavailability, increased oxidative stress, inflammation, and vascular remodeling (67, 72). These alterations can impair neurovascular coupling, limiting the ability to match blood flow to metabolic demand and contributing to cognitive decline. Overall, these past studies support that peripheral microvascular function may serve as a sentinel marker of systemic vascular health, with direct relevance to cerebral hemodynamics and brain structure.

Excitingly, microvascular function appears to retain substantial plasticity across the lifespan, even in the presence of age-related macrovascular changes (66). This distinction is clinically meaningful, as interventions capable of reversing large artery stiffness remain limited (73, 74), whereas microvascular function is highly responsive to lifestyle and pharmacological strategies (66, 75, 76). Although persistent macrovascular dysfunction may continue to expose the cerebral microvasculature to greater pulsatile stress, improvements in microvascular function are still expected to enhance local perfusion and vascular responsiveness, thereby attenuating downstream cerebrovascular dysfunction and supporting cognitive health. However, to be clear, these adaptations are unlikely to fully offset the adverse hemodynamic consequences of persistent large-artery stiffness. It is also important to acknowledge that peripheral and cerebral microvascular responses to intervention may differ because of distinct local regulatory mechanisms (e.g., cerebral autoregulation), although both remain components of an integrated vascular network influenced by systemic adaptations and interorgan communication. As such, the microvasculature may represent a viable target for mitigating cerebrovascular dysfunction and preserving cognitive function. However, further work is needed to determine which assessment techniques are most predictive and to optimize interventions to delay or prevent neurodegeneration, specifically those related to VCID.

2. Arterial Stiffness and Pulsatile Hemodynamics

Beyond the microvasculature, large conduit arteries are essential for buffering pulsatile flow, and dysfunction in this system has notable consequences for cortical integrity and cognitive function. In response to aging and cardiometabolic disease, there is a loss of arterial compliance that increases the transmission of flow pulsatility into distal vascular beds, including the cerebral circulation (23, 38-41, 77-80). Although some loss of elasticity in large conduit arteries is unavoidable with aging, arterial stiffness is also largely influenced by other factors, such as lipid levels, inflammatory markers, and genetic variants, which offer a potential window of opportunity to mitigate adverse outcomes. This has important implications for the overall brain health and function, as the cerebral microvasculature is notably vulnerable to excessive pulsatile stress.

Experimental models provide clear evidence of this relationship (77). In mice, transverse aortic constriction–induced elevations in pulse pressure lead to cerebral hypoperfusion, microvascular rarefaction, BBB disruption, and cognitive impairment, with more pronounced effects in AD models (77, 81). These data suggest that elevated pulsatility can independently impair cognition and worsen existing neuropathology. In humans, large-scale cohort data support these observations, such that the Atherosclerosis Risk in Communities–Neurocognitive Study (ARIC; n = 3,703) demonstrated that greater arterial stiffness is associated with increased white matter hyperintensity burden, greater brain atrophy, and reduced cognitive function (40). Moreover, individuals with the highest arterial stiffness showed greater longitudinal declines in cognitive function over a 20-year period, suggesting that increased arterial stiffness may accelerate this cascade. In support of this notion, recent evidence indicates that the inverse relationship between circulating NfL and both episodic and working memory is mainly observed in individuals with elevated arterial stiffness (i.e., carotid-femoral pulse wave velocity), further highlighting that vascular aging may amplify the consequences of neurodegeneration (48). The underlying mechanism involves the progressive loss of the aorta’s buffering capacity, such that under normal conditions, the aorta acts as a reservoir, storing energy during systole and releasing it during diastole (i.e., Windkessel effect) (82). With aging, structural changes occur, including elastin fragmentation and increased collagen deposition, which ultimately reduce arterial compliance, allowing greater pulsatile energy to propagate downstream (39-41). Cerebral vessels have limited capacity to buffer these forces and are thus clearly susceptible to injury. As a result, increased pulsatility promotes microvascular damage manifesting as white matter hyperintensities, lacunar infarcts, and microbleeds, all of which are linked to cognitive decline (41, 79, 80). Over time, these insults can disrupt axonal integrity, impair neurovascular coupling, and contribute to cortical thinning and regional brain atrophy. It is critical to note that structural components of arterial stiffness may become difficult to reverse once established, as extracellular matrix cross-linking can render the mechanical properties of the arterial wall relatively fixed (73, 74). Although exercise and other interventions may improve vascular function and reduce blood pressure–dependent components of stiffness, they likely do not fully restore intrinsic arterial elasticity.

Given the lack of robust methods to reverse arterial stiffness, we propose, based on previous data (38), that attention should move toward the microvasculature as a modifiable target to mitigate the downstream effects of lost compliance. Healthy microvessels possess compensatory mechanisms, including endothelial-mediated vasodilation, that can buffer increases in pulsatile flow. However, when microvascular function is impaired, these protective mechanisms are diminished, allowing greater transmission of pulsatile energy into vulnerable tissues such as cerebral white matter (83, 84). Observational data support this interaction, demonstrating that impaired microvascular reactivity is associated with greater pulse pressure and arterial stiffness (84). These data underscore the importance of considering macro- and microvascular function as complementary, rather than independent, contributors to brain health. Considering this, strategies to preserve or improve microvascular function may attenuate the harmful effects of arterial stiffening (85), especially when implemented early in the disease trajectory. That is, although protection from pulsatile pressure is primarily provided by the Windkessel function of the large elastic arteries, when this buffering capacity is diminished by arterial stiffening, intact microvascular function and autoregulatory mechanisms may help limit the transmission of excessive pulsatile energy to tissue capillary beds, thereby reducing susceptibility to end-organ damage. Furthermore, because microvascular remodeling can increase peripheral vascular resistance and contribute to a positive feedback loop that exacerbates arterial stiffening, preserving microvascular health via lifestyle interventions (e.g., exercise and diet) may also help slow the progression of vascular aging. For instance, seven days of L-citrulline supplementation reduced brachial-ankle pulse wave velocity in middle-aged men by ~8.5%, most likely reflecting improved NO-mediated vascular function rather than structural remodeling of the arterial wall or reductions in blood pressure (86). However, it remains unclear to what precise extent preserved or augmented microvascular function can attenuate the negative consequences of arterial stiffness.

3. Cerebral blood flow and blood-brain barrier integrity

The BBB represents a key point of intersection between the peripheral circulation and the CNS, serving not only to maintain brain homeostasis through tightly regulated molecular exchange but also as a dynamic signaling interface that regulates peripheral-to-central communication (1, 65). Structurally, the BBB is formed by specialized endothelial cells connected by tight junctions and supported by pericytes, vascular smooth muscle cells, and astrocytic endfeet, collectively comprising the neurovascular unit (1, 65). Thus, the BBB should not be viewed solely as a passive barrier but rather as an active regulatory structure that integrates vascular, metabolic, neural, and immune-derived signals. Disruption of BBB integrity is increasingly recognized as an early contributor to cognitive decline (24). Even in healthy aging, increased BBB permeability is detectable in regions such as the hippocampus, and BBB dysfunction can occur independently of classical AD pathology, suggesting that vascular mechanisms represent a distinct pathway to cognitive impairment (24).

Peripheral cardiometabolic risk factors play a central role in cerebral blood flow and BBB disruption (1, 65), whereby chronic low-grade inflammation associated with obesity, type 2 diabetes, and cardiometabolic syndromes reduces cerebral blood flow, alters endothelial signaling, and compromises tight-junction integrity through cytokine-mediated pathways (Figure 2). These changes facilitate leukocyte adhesion and transmigration, which exacerbates neuroinflammatory responses (e.g., release of IL-1β and TNF-α). Further, experimental evidence underscores the impact of these processes, such that in models of type 2 diabetes, hyperglycemia-induced inflammation increases BBB permeability, accompanied by endothelial dysfunction, microglial activation (pro-inflammatory), pericyte loss, and tight junction disruption, changes that are strongly associated with cognitive deficits (87). Increased permeability allows circulating proteins (e.g., fibrinogen) and inflammatory mediators (e.g., TNF-α) to enter the brain parenchyma, disrupting neuronal signaling and neurovascular coupling. Interestingly, the degree of BBB leakage correlates with inflammatory activation and predicts accelerated cognitive decline, with effects comparable to several years of aging (88). These processes operate within a feed-forward cycle, through which peripheral inflammation and metabolic dysfunction impair vascular function and BBB selectivity, facilitating the entry of inflammatory mediators into the CNS and further worsening neuroinflammation and neuronal injury (65). This cycle highlights the interconnected nature of peripheral and central processes in driving the loss of brain health.

Figure 2.

This schematic illustrates the proposed interaction between cardiometabolic disturbances, peripheral inflammation, and cerebrovascular dysfunction in the progression of dementia. Cardiometabolic impairments and chronic peripheral inflammation may engage in a bidirectional feed-forward cycle that progressively disrupts cerebrovascular integrity and brain homeostasis. At the level of the cerebral microcirculation and blood–brain barrier (BBB), these disturbances contribute to impaired cerebral blood flow, endothelial dysfunction, BBB disruption, and altered neurovascular signaling. Reduced oxygen and nutrient delivery, together with increased BBB permeability and infiltration of circulating inflammatory factors, may exacerbate neuronal dysfunction and neurodegenerative processes. Together, these vascular and inflammatory perturbations are proposed to contribute to cognitive decline and increase susceptibility to dementia. Created in BioRender. Nelson, A. (2026) https://BioRender.com/iw6f0yz

The integrity of the BBB is closely linked to overall vascular health, as seen by the notion that cardiometabolic risk factors (e.g., physical inactivity and/or poor diet) and broader social determinants all influence vascular function, including cerebral blood flow, and, by extension, BBB stability (1, 3, 25). The loss of BBB integrity alone can impair cognition, as demonstrated by associations between increased permeability and deficits across multiple cognitive domains, independent of amyloid and tau pathology (24). Given its influential role in maintaining brain health, the BBB represents a promising target for intervention. Strategies that reduce inflammation, improve endothelial function, and enhance vascular health, like exercise, dietary modification, and other nonpharmacological approaches, could help preserve cerebral blood flow and BBB integrity and delay the onset of cognitive decline. Together, these observations indicate that the BBB links peripheral vascular health to brain integrity through its central role in regulating peripheral-to-central signaling. Targeting vascular health across multiple levels may therefore represent a promising approach to preserving brain health and cognitive function.

Skeletal muscle determinants of brain health

1. Skeletal muscle mass, strength, power, and endurance

Skeletal muscle, the largest organ system in the human body, plays roles extending beyond just movement and metabolic regulation by also contributing to cardiovascular and brain health throughout the lifespan (31, 32, 89, 90). This contribution is reflected in various outcomes from efforts to promote and preserve skeletal muscle function, which commonly lead to a reduced risk of CVD (91, 92) and neurodegenerative diseases (93), including ADRDs (31, 43, 89), consistent with the close coupling between vascular and cerebral health (1, 2, 38, 65, 70). Recent data suggest that meeting physical activity guidelines may reduce AD risk, potentially by protecting against temporal lobe atrophy in older adults (94). Furthermore, additional new findings indicate that 90-119 min/week of long-term resistance training was associated with a 27% lower mortality from neurological disease (i.e., a non-linear dose-response), independent of aerobic activity (93). Although the precise mechanism linking physical activity and brain health remains incompletely defined, accumulating evidence, such as a recently identified mechanical coupling between the abdominal musculature and the CNS (95), continues to support the concept that skeletal muscle can influence brain physiology through multiple interconnected pathways. Moreover, exercise, primarily resistance training, provides a potent stimulus to improve skeletal muscle mass, strength, and power (96), even in older adults (97); however, the associated adaptations do not appear to contribute equally to health outcomes. Rather, indices of muscle function, especially strength and power, are consistently more predictive of cognition, vascular health, and mortality than muscle mass alone (33, 98, 99).

Skeletal muscle mass.

To quantify skeletal muscle mass, most measures rely on indirect estimates of lean mass (e.g., bioelectrical impedance spectroscopy, underwater weighing) or lean soft tissue (LST) mass (e.g., dual-energy X-ray absorptiometry; DXA), which reflect a heterogeneous tissue compartment rather than muscle exclusively (97, 100). More precise methods for estimating skeletal muscle mass do exist, including magnetic resonance imaging (MRI), computed tomography (CT), and D3-creatine dilution, but these approaches present several challenges in large epidemiological studies. Consequently, associations between “skeletal muscle mass” and brain health should be interpreted with some caution; nevertheless, epidemiological evidence still supports a modest, and perhaps meaningful, relationship between LST and cognitive outcomes. For example, data from the French Epidemiology of Osteoporosis study (EPIDOS; n > 7,000 women) showed that individuals in the lowest LST category had ~43% higher odds of cognitive impairment than those in the highest category (101). Similarly, LST is positively associated with MRI-derived whole-brain volume, pointing to possible parallel atrophy of muscle and brain tissues (102). These correlation-based findings may be influenced by shared underlying mechanisms that contribute to concurrent declines in muscle and cognitive function, including hormonal dysregulation, heightened systemic inflammation (both low-grade chronic and age-associated), and increased oxidative stress (43, 103). Consistent with this, our previous findings led us to hypothesize that loss of skeletal muscle mass may be more detrimental to healthy aging than the accumulation of fat mass (70). These past results reported a positive correlation between LST and reactive hyperemia, whereas no such relationship was observed between fat mass and peripheral vascular function.

Contributing to these shared mechanisms is the age-related decline in satellite cells, which are a resident stem cell population responsible for skeletal muscle fiber repair, regeneration, and growth. Progressive reductions in satellite cell number and function impair muscle regenerative capacity, compounding the effects of physical inactivity to accelerate the loss of muscle mass and function characteristic of sarcopenia (104). Sarcopenia is increasingly recognized as an independent risk factor for cognitive decline and ADRD, with disrupted myokine secretion proposed as a central mechanistic link (43). Physically active, well-maintained muscle sustains the release of neuroprotective signals that support brain health, whereas the atrophied, metabolically compromised muscle characteristic of sarcopenia exhibits substantially diminished myokine output, thereby impairing muscle-brain communication and contributing to a neuroinflammatory environment associated with cognitive deterioration (105). Although direct evidence is limited, greater skeletal muscle mass (i.e., hypertrophy) may increase the amount of metabolically active tissue available to support exercise-induced myokine signaling (e.g., BDNF) (106, 107), most notably when accompanied by improvements in mitochondrial and neuromuscular function (36). For instance, resistance exercise has been shown to increase circulating BDNF, and greater lean mass is associated with larger exercise-induced BDNF responses (106, 107). Thus, muscle mass may amplify the effects of functional characteristics on long-term brain health.

Functional characteristics of skeletal muscle.

Muscle strength, defined as the capacity to generate force, and muscle power, reflecting the ability to generate force rapidly, are characteristics that provide insight into the state and functionality of the neuromuscular system. Associated measures (e.g., isokinetic leg strength) are increasingly recognized as sensitive indicators of health and useful in aging populations. For instance, strength is consistently associated with reduced risk of CVD, premature mortality, and cognitive decline, and even simple measures (e.g., grip strength) correlate well with neuromuscular function and physical activity patterns (91, 108, 109). In a prospective cohort of more than 900 older adults, greater baseline strength was associated with a lower risk of AD and a slower rate of cognitive decline over four years, independent of key confounders, including physical activity and APOE-ε4 carriage (110). Perhaps most importantly, higher strength was also associated with reduced risk of MCI, suggesting that declines in muscle function may precede overt cognitive impairment.

In addition to muscle strength, previous investigators have considered muscle endurance, defined as the ability to sustain exercise over time (e.g., repetitions to failure). Notably, substantially less data are available describing the relation between skeletal muscle endurance and overall cognitive health. However, age-related declines in endurance appear to occur in parallel with, or perhaps before, declines in cognition and cerebrovascular function, which may share vascular aging as an underlying cause (111). This overlap may, in large part, be due to reductions in NO bioavailability, endothelial-dependent vasodilation, and perfusion, which impair oxygen delivery to both the recruited muscle fibers and the cerebral tissue, thereby contributing to diminished fatigue resistance, disrupted neurovascular coupling, and white matter dysfunction (111). Interestingly, six weeks of exercise plus beet root juice (i.e., a rich source of dietary inorganic nitrate, an NO donor) may potentiate the neuroplastic benefits of exercise compared with exercise alone (112). Thus, these findings highlight the potential critical role of NO bioavailability. Prior work has also highlighted the role of aerobic endurance, as captured by cardiorespiratory fitness; however, the current review aimed to evaluate skeletal muscle endurance rather than markers such as maximal oxygen uptake ($\stackrel{.}{\mathrm{V}}{\mathrm{O}}_{2\max }$). Direct evidence linking skeletal muscle endurance to brain health remains limited, but mechanistic studies suggest that endurance-oriented resistance exercise may influence biological pathways related to cognitive health. For example, Ross et al. investigated the effects of muscular endurance resistance exercise (i.e., three circuits with six exercises and 15 repetitions per exercise) on circulating endothelial progenitor cells (EPCs) and angiogenic factors, which elicited an increase in EPCs and transient elevations in vascular-derived growth factors (VEGF-A, C, and D) (113). That is, these findings suggest that this style of resistance exercise may promote favorable vascular remodeling through the identified exercise-induced transient increase in circulating factors. Additional research is needed to confirm these findings and to determine whether endurance resistance exercise-based prescriptions are uniquely beneficial compared with other forms of strength training (e.g., high-load, low-repetition). Interestingly, however, 12 weeks of high-load (low-repetition) vs. low-load (high-repetition) resistance training completed to volitional failure in recreationally active young men yielded comparable microvascular adaptations (e.g., capillary-to-fiber ratio) (75). Thus, perhaps these adaptations are more related to achieving a certain level of effort during exercise as opposed to a specific style of strength training.

Perhaps unsurprisingly, there is considerably more available evidence linking cardiorespiratory fitness, as opposed to skeletal muscle endurance, to dementia risk (114-116). For instance, it was recently shown that individuals who moved from an unfit to fit status demonstrated ~50% lower risk of incident dementia, and each 1-metabolic equivalent of a task (MET) increase in fitness was associated with a 16% lower risk of incident dementia (117). Accordingly, in general, improving “endurance” and garnering the associated adaptations are meaningful goals that are likely to promote brain health. This, in large part, is driven by improvements in metabolic health through reduced inflammatory load (e.g., C-reactive protein [CRP]) and enhanced insulin sensitivity, which may collectively support positive changes in cerebral blood flow and function (1, 30, 65). To achieve these benefits, and considering the FITT framework (frequency, intensity, time, and type), current recommended exercise prescriptions for brain health emphasize activity as often as possible, 140 minutes of moderate or 75 minutes of vigorous exercise per week, and a combination of activities such as aerobic (e.g., walking and hiking), strength training, and Tai Chi or yoga to facilitate muscle-to-brain signaling (90). Following this FITT prescription should not only improve the contractile proteins essential for muscle strength and endurance but also the neural components underlying muscle function, as evidenced by changes in NMJ integrity and motor neuron function (97, 118).

Beyond strength and endurance, muscle power appears to provide additional insight into brain health, with power-dependent tasks, such as chair-rise performance, strongly associated with functional and cognitive outcomes (33, 44, 45). Cross-sectional data have shown that lower-limb power is positively associated with global cognition and executive function, including performance on tasks like the Stroop test (45). Further, a complementary measure related to muscle power is the rate of force development (RFD), which has been stated to reflect the speed of motor unit recruitment and initial neural drive (119). Interestingly, RFD has been shown to correlate more strongly with cognitive performance than traditional strength measures (120), suggesting that rapid force production may better capture central neural processes relevant to brain function. These findings support the notion that muscle power may provide unique insights into brain health beyond those afforded by strength and/or endurance alone. Because muscle–brain crosstalk depends on effective skeletal muscle recruitment, these observations may point to the involvement of lower motor neurons within integrated spinal and supraspinal networks that coordinate muscle function and may help preserve brain health. Although these past studies support the importance of a direct muscle–brain axis, skeletal muscle also communicates with the brain indirectly by releasing factors into the systemic circulation that influence vascular and neural function. Thus, continued emphasis should be placed on the notion that these pathways operate in concert, with the muscle–vascular–brain axis providing a broader context through which peripheral adaptations support brain health.

Overall, aside from a couple of studies showing exercise-induced adaptations relevant to cognitive and brain health (75, 113), much of the evidence presented in this section was correlational or cross-sectional; thus, strong directional interpretations may be inappropriate or underdeveloped. To strengthen the proposed link between skeletal muscle function and cognitive outcomes, a previous systematic review summarizing 18 resistance training studies should also be considered, as the included interventions consistently demonstrated favorable effects on brain and cognitive health (121). For example, the review highlighted evidence that gains in lower-body strength following progressive resistance training mediated improvements in global cognitive performance (122), while improvements in isokinetic knee flexion torque mediated improvements in executive function (123). Furthermore, the studies summarized in the systematic review reported that these cognitive improvements frequently occurred alongside functional and structural brain adaptations, including greater activation of the left anterior insula, reduced progression of white matter lesions, and increased cortical thickness, collectively providing experimental evidence supporting a directional relation between skeletal muscle adaptations and brain health (121).

2. Role of the motor neuron

Muscle strength and power ultimately depend on the motor neuron and NMJ, which together form the final pathway linking central neural drive to peripheral force production (97). As such, declines in muscle function may reflect upstream neural dysfunction rather than solely intrinsic muscle deficits (e.g., reduced contractile protein content). Lower motor neurons are uniquely positioned at the intersection of the CNS, peripheral vasculature, and skeletal muscle. Their long axons, high energetic demands, and reliance on continuous oxygen delivery may render them particularly vulnerable to aging, metabolic dysfunction, and vascular impairment (124-126). New evidence even suggests that declines in motor unit number, disrupted denervation–reinnervation balance, and impaired neuronal conduction may parallel, or even precede, cognitive decline and frailty, ultimately contributing to the loss of independence (31, 34, 35, 37, 127, 128).

Experimental models further support this concept. In 5xFAD mice (a widely used transgenic AD model with App overexpression under the Thy1 promoter), reductions in force production were observed during nerve stimulation but not during direct muscle stimulation, implying early impairments in peripheral motor nerve conduction and transmission, not deficits in muscle contractile capacity (31, 32, 34, 129). The impaired transmission also emerged before overt cognitive impairment and significant amyloid pathology, suggesting that peripheral neuromuscular dysfunction may be a part of early disease-related changes. Most recently, this group also reported proteomic findings that further supported this concept, showing that the onset of peripheral neuromuscular dysfunction coincides with extensive remodeling of the sciatic nerve proteome, notably in pathways related to mitochondrial function and turnover, while cognitive function remained unaltered (129). Similarly, recent findings from human-induced pluripotent stem cell-derived NMJ models of familial AD showed that motor neuron dysfunction may precede structural or muscular deficits (35). Motor neurons harboring presenilin-1 (PSEN1; a familial AD-associated gene) or amyloid precursor protein (APP) mutations exhibited time-dependent alterations in excitability, transitioning from early hyperexcitability to later hypoexcitability with reduced firing capacity. These changes appeared to impair NMJs and increase fatigue during repeated stimulation, despite preserved NMJ number and intact muscle responses to direct stimulation. In conjunction, these findings indicate that early, progressive impairments in motor neuron function are at least associated with AD hallmarks in experimental models. Observational studies further support this concept, as slower nerve conduction and reduced motor unit function were correlated with cognitive impairment and dementia risk (37, 127). Taken together, and as Brisendine and Drake hypothesized (see recent topical review (32)), these findings support the concept that peripheral motor neuron dysfunction may precede, and perhaps even contribute to, cognitive decline. Additional studies in humans are still needed to determine the time course of motor neuron dysfunction in relation to sporadic AD and/or cognitive decline.

Mechanistically, motor neuron activity appears to regulate signaling originating in skeletal muscle. Neuronal innervation enhances myokine and EV release, with activity-dependent increases in the expression of factors such as IL-6 and BDNF (36). These responses are closely linked to skeletal muscle oxidative metabolism, as indexed by PGC-1α mRNA expression, a transcriptional coactivator involved in mitochondrial biogenesis as well as NMJ maintenance and remodeling. Furthermore, EVs transport miRNAs, small noncoding RNA molecules that regulate gene expression by altering messenger RNA translation and stability. These miRNAs reportedly influence neural development, synaptic transmission, and plasticity, with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, a bioinformatic approach used to identify enriched molecular signaling pathways, revealing biological processes relevant to neural network formation. Thus, these signals influence not only muscle metabolism but also central neuronal function, including synaptic activity and neurogenesis. These findings, therefore, support a model in which motor neuron function actively shapes muscle–brain communication rather than serving solely as a passive marker of nervous system integrity.

3. Myokines

Skeletal muscle can act as an endocrine organ, releasing a full array of signaling molecules collectively termed myokines that serve as key mediators of interorgan communication (14, 18). For this review, we use this framework broadly to encompass canonical myokines, muscle-derived metabolites, and muscle EV-associated cargo involved in interorgan communication. These muscle-derived signals act through endocrine, paracrine, and autocrine pathways to directly and indirectly influence the CNS, including the BBB, and represent an emerging mechanism that links physical activity to brain health (14, 18, 130). Among the most studied myokines is BDNF, which plays a central role in synaptic plasticity, neurogenesis, and memory formation (20, 130). Exercise increases BDNF through both direct and indirect pathways, including lactate-mediated signaling (131), whereby muscle-derived lactate crosses the BBB and stimulates hippocampal BDNF expression (22, 132). El Hayek and others (132) clearly demonstrated in adult male mice that pharmacological inhibition of lactate transport across the BBB abolishes the exercise-induced increase in BDNF, revealing that lactate is required for this response. In addition, peripherally derived BDNF participates in retrograde signaling at the NMJ, modulating presynaptic function and efficacy (63) and contributing to mitochondrial remodeling and maintenance through pathways involving AMPK activation (133). Despite these critical roles, BDNF levels decline with age (134), but lifestyle intervention can favorably change this trajectory, especially those that promote skeletal muscle and vascular function (17, 18, 30, 32, 43, 135).

Independent of its BDNF-associated signaling, lactate itself exerts pleiotropic effects on brain health. Exercise-induced elevations in circulating lactate can cross the BBB via monocarboxylate transporter 1, facilitating lactate uptake and utilization within the CNS (131, 132, 136). Within the brain, lactate functions not only as an energy substrate but also as a signaling metabolite that modulates astrocyte-neuron metabolic coupling (137). Exercise-associated increases in neuronal activity linked to motor control and sensory processing stimulate glutamatergic signaling, glycogenolysis, and enhanced astrocytic glucose uptake, all of which supporting neuronal energetic demands and synaptic activity (138). Beyond its metabolic role, lactate has increasingly been recognized as a mediator of neurobiological adaptation, influencing angiogenesis, neurogenesis, neuroinflammatory processing, synaptic plasticity, and cerebrovascular endothelial function (139-142). Importantly, lactate has emerged as a potential therapeutic target in neurological and neuropsychiatric disorders, including ADRDs and traumatic brain injury (141, 143).

In addition to BDNF and lactate, several other peripherally released myokines and exercise-induced factors contribute to muscle–brain crosstalk. These include cathepsin B, irisin, IL-6, and clusterin, which have been linked and/or hypothesized to be involved with several relevant processes, including neurogenesis, regulation of neuroinflammation, and synaptic plasticity (20, 135, 144-147). Skeletal muscle also regulates circulating neuroactive metabolites (18) such that there is a PGC-1α–dependent shift in kynurenine metabolism to promote the conversion of neurotoxic kynurenine into kynurenic acid. This is relevant as an elevated kynurenine/tryptophan ratio is associated with increases in key AD biomarkers, such as phosphorylated tau, suggesting that kynurenine-tryptophan dysregulation may contribute to AD pathogenesis (148). This pathway has been shown to be responsive to acute exercise (149) and is impaired in metabolic and neurodegenerative disease states, again connecting skeletal muscle health to both metabolic and neurocognitive outcomes. For example, Joisten and others (150) performed a secondary analysis of a prospective single-blind randomized controlled trial in people with multiple sclerosis and reported that, compared with moderate continuous exercise, high-intensity interval training (HIIT) elicited a larger and more sustained reduction in plasma neurofilament light chain (NfL) (i.e., a biomarker of neuroaxonal damage), while simultaneously promoting a neuroprotective shift in kynurenine metabolism. Taken together, exercise may not act solely by modifying AD pathology itself, but rather by mitigating neurodegenerative processes, thereby increasing resilience to disease and delaying the onset of cognitive impairment.

An additional mechanism for interorgan signaling extends beyond soluble factors and metabolites to include EVs released from skeletal muscle, with cargo enriched for proteins and miRNAs involved in metabolism, inflammation, and neural function (16, 151, 152) (Figure 3). Recent work by Vann et al. (151) revealed that EV cargo is selectively packaged (e.g., “exercise signatures”) rather than a random sampling of muscle contents, and that they can regulate both local and systemic biology, including motor neuron function. Pathway analysis revealed enrichment for signaling networks, including PI3K/AKT, MAPK, and FoxO, which are associated with cellular metabolism, survival, and plasticity. Kargl and coauthors demonstrate that oxidative skeletal muscle-derived EVs increase the angiogenic potential of endothelial cells through enhanced phosphorylation of eNOS (153), while Zhang and coauthors report that RYR1+ skeletal muscle-derived EVs detected in circulating plasma are associated with improvements in insulin signaling across participants subjected to aerobic exercise interventions (154). Collectively, these findings show that skeletal muscle-derived EVs function as selectively encoded signaling units that transmit exercise-dependent information to local and distant tissues, consequently contributing to systemic metabolic adaptations and to neuromuscular and neural function (151). Lin and coauthors support this notion, demonstrating that muscle-derived EVs enhance synaptic plasticity and alleviate cognitive impairment in rodents (155). Mechanistically, it was shown that miRNA-17/20a-5p binds to DEPTOR (DEP-domain containing mTOR-interacting protein), thereby activating the mTOR pathway in the hippocampus. Critically, unlike freely circulating myokines or metabolites, EVs provide a protected, directed mechanism for interorgan communication through target-specific binding via the target cell membrane (156), enabling coordinated delivery of molecular cargo to specific recipient tissues rather than acting stochastically. Of note, the synthesis and signaling of these factors are meaningfully influenced by mitochondrial function and redox balance (157), positioning mitochondrial function as a central determinant of muscle–vascular–brain communication and a key focus of the following section.

Figure 3.

This conceptual illustration depicts mechanisms underlying skeletal muscle–vascular–brain communication and the role of exercise in promoting systemic and cognitive health. Skeletal muscle communicates with the peripheral vasculature and brain through the release of cytokines, myokines, metabolites, proteins, extracellular vesicles (EVs), and mitochondrial-derived peptides, all of which can contribute to interorgan signaling. Exercise and physical activity stimulate the production and release of signaling molecules, including brain-derived neurotrophic factor (BDNF) and EV-associated cargo, that influence neuroplasticity, mitochondrial function, and inflammation. Concurrently, exercise promotes vascular adaptations, including endothelial nitric oxide synthase (eNOS) activity, angiogenesis, and tissue perfusion, facilitating the delivery of circulating factors. The vasculature also contributes to the clearance of metabolic waste products. These integrated muscle-, vascular-, and exercise-mediated signaling pathways are leading candidates to support brain health and mitigate age-related neurodegenerative and cardiometabolic dysfunction. Created in BioRender. Vann, C. (2026) https://BioRender.com/ghyr3ou

4. Mitochondrial function

Mitochondria are not only essential energy hubs within our cells but also play a critical role in intra- and extracellular communication. Although adenosine triphosphate (ATP) production through oxidative phosphorylation is the quintessential “mitochondrial function”, mitochondria also regulate redox balance (158), oxidative and reductive stress (159), intracellular calcium handling (160), production of mitochondrial-derived peptides (MDP) (161), and ultimately regulate apoptosis. Not surprisingly, “mitochondrial dysfunction” is one of the 12 Hallmarks of Aging (162). For example, skeletal muscle mitochondrial oxidative capacity measured both in vivo (163) and in vitro (164) has consistently been shown to decline with age. Recent data from the Study of Muscle, Mobility and Aging (SOMMA) suggest these age-related declines in skeletal muscle mitochondrial oxidative capacity contribute to impairments in physical function, perceived fatigue (e.g., fatigability), and perhaps even cognitive function (165-167). Specifically, SOMMA data (~850 adults, aged: 76 yrs, 59% female) revealed that each 1 SD decrement in maximal skeletal muscle oxidative phosphorylation capacity was associated with a 1.7-point lower score on the Digit Symbol Substitution Test, indicating slower processing speed, independent of age, sex, muscle area, hypertension, diabetes, and body mass index (166). However, the exact mechanisms linking age-related declines in skeletal mitochondrial function to declines in cognitive function remain to be fully elucidated.

Like skeletal muscle, the brain is a highly energy-demanding tissue composed of multiple cell types, including neurons and glial cells (e.g., astrocytes). Indeed, at rest the mass-specific metabolic rate of the brain is considerably higher than that of skeletal muscle and declines with age (168). Moreover, mitochondrial dysfunction is commonly observed in the brains of several preclinical models of ADRD (169-172) as well as humans with ADRD (173-175). Insulin resistance is commonly associated with age-related mitochondrial dysfunction in skeletal muscle and may play a role in the brain. Recent data also suggest that insulin resistance is not confined to the periphery but can develop in the brain (176, 177), potentially leading to reduced glucose oxidation and broader neurodegenerative processes. For instance, UK Biobank data, combined with a meta-analysis of 34 studies, led to a report that type 2 diabetes is associated with cognitive deficits, gray matter atrophy, and functional brain changes that overlap with patterns observed during aging, suggesting that this condition may accelerate brain aging through shared pathways (178). Although insulin has been shown to be a key mediator of mitochondrial oxidative capacity in skeletal muscle (163, 179-181), its role in mediating mitochondrial oxidative capacity and other mitochondrial functions in the brain remains incompletely understood, in particular with respect to the development of age-related cognitive impairments. Aging is also associated with progressive declines in brain glucose utilization, particularly within higher-order cortical regions involved in cognition (182). Of interest, the reductions in glucose utilization appear to be confined to region-specific reductions in “aerobic glycolysis”, while (mitochondrial) oxidative glucose utilization appears preserved in the absence of overt age-related neuropathology, suggesting that diminished region-specific “aerobic glycolysis” may represent a fundamental feature of normative brain aging rather than solely a consequence of neurodegenerative disease (182). Finally, similar studies are needed to determine whether further impairment in (mitochondrial) oxidative glucose utilization is what drives the transition from normal cognitive aging to the development of ADRDs.

Relevant to the current review, there may be a mechanistic link between skeletal muscle and the brain that regulates and/or coordinates changes in mitochondrial function and cognitive function with aging. To illustrate, the Baltimore Longitudinal Study (BLS) recently demonstrated that higher skeletal muscle mitochondrial oxidative capacity, quantified using in vivo post-exercise mitochondrial phosphocreatine recovery rate constants, was associated with a ~50% lower hazard of developing MCI/dementia (89). Moreover, additional analysis of the BLS further suggested that higher skeletal muscle mitochondrial oxidative capacity was associated with slower progression of brain aging and preservation of key cortical and subcortical regions involved in motor and cognitive (e.g., memory) function over longitudinal follow-up (183). In support of the BLS data, an elegant study by Morris et al. (184) revealed that participants with MCI had lower in situ skeletal muscle mitochondrial oxidative capacity than cognitively healthy controls. Notably, participants treated with Donepezil, a cholinesterase inhibitor commonly used to manage ADRDs, had normal mitochondrial oxidative capacity, which may reflect a direct effect on skeletal muscle mitochondria or indirect effects mediated by improvements in cognitive function (184). As such, the mechanisms underlying the association between age-related changes in skeletal muscle mitochondrial function and cognitive impairment may be bidirectional.

Chronic exercise, especially in mid- and late-life, has been shown to reduce the risk of dementia and ADRDs (7, 12, 185-187). As previously defined, this includes meaningful, individualized exercise prescriptions that consider the FITT framework (56), thereby ensuring an adequate and regular stimulus. Notably, there does not appear to be a clear dose-response relationship, but a systematic review and meta-analysis suggested that older adults with cognitive impairment generally benefited most from shorter, more frequent exercise sessions (188). Accordingly, the mechanisms underlying the neuroprotective effects of exercise remain poorly elucidated, as they are likely complex and multifactorial. Here, we focus on novel MDPs that could link exercise to improvements in brain mitochondrial function and, in turn, to improved cognitive function in the context of aging and ADRDs. Dr. Pinchas Cohen led the discovery and characterization of several MDPs relevant to brain aging and cognitive function. For example, treatment with the humanin analog HNG improved performance in both the Barnes maze and Y-maze in aged mice, suggesting preservation of spatial learning and memory (189). HNG treatment also attenuated Aβ-induced mitochondrial ROS production in isolated neuronal mitochondria and reduced markers of microglial activation and systemic inflammation, supporting a neuroprotective role for humanin signaling (189). Further, individuals carrying the mitochondrial SNP rs2854128, which was associated with lower circulating humanin concentrations, exhibited accelerated cognitive aging, notably among African American participants (189). Again, as previously suggested, HIIT may be an effective strategy to leverage specific pathways linking the periphery and brain health, as it has been shown to transiently increase circulating humanin levels (190). As detailed above, there is a strong link between insulin resistance and mitochondrial function in the brain, which Muzumdar and colleagues leveraged using a state-of-the-art clamp technique, showing that both central and peripheral administration of humanin improved central insulin sensitivity in Zucker diabetic rats (191). Unfortunately, the study did not measure changes in mitochondrial function to directly test the impact of humanin-induced improvements in central insulin action on mitochondrial function. Secondly, MOTS-c (mitochondrial open reading frame of the 12S rRNA-c) is another recently discovered MDP associated with changes in insulin sensitivity and physical function (192), which may also directly and/or indirectly affect cognitive aging. Of note, an acute bout of HIIT has been shown to increase MOTS-c expression in muscle and, concomitantly, circulating concentrations in humans. One challenge is that native MOTS-c does not readily cross the BBB; however, engineered cell-penetrating analogs, when administered intranasally or intravenously, have demonstrated central neuroprotective effects, including reduced neuroinflammation and improved cognitive performance in models of ADRDs (193). Finally, small humanin-like peptide 2 (SHLP2) is a third MDP with potential neuroprotective effects (194, 195). For example, exposure of primary mouse cortical neurons to 10 μM Aβ increased LDH leakage, an indicator of neuronal injury, relative to vehicle-treated cells; however, this Aβ-induced toxicity was attenuated by SHLP2 treatment in a dose-dependent manner (194). Despite the potential and excitement surrounding these findings, additional studies are still needed to determine whether SHLP2 contributes to age-related declines in cognitive function.

Integrated muscle–vascular mechanisms supporting brain resilience

As discussed throughout the first two sections of this review, skeletal muscle, the peripheral vasculature, and mitochondria release numerous bioactive factors into the circulation, including myokines, EVs, MDPs, metabolites, and inflammatory mediators. These circulating signals can exert beneficial or detrimental effects as they travel to and interact with neighboring or distant tissues. Thus, blood should be viewed as a complex and dynamic internal environment containing bioactive molecules that continually influence tissue function throughout the body. This collection is commonly referred to as the “circulating milieu” and has been robustly shown to be meaningfully affected by the health, age, and lifestyle of the respective organism. Early compelling evidence from parabiosis, a surgical experimental model in which the circulatory systems of two separate organisms are connected (e.g., a young and an old mouse), indicated that exposure to a youthful circulating milieu restored regenerative signaling and tissue repair in aged muscle. For example, few to no regenerated myotubes originated from young donor cells, and the enhanced regeneration coincided with restoration of Delta/Notch signaling (i.e., a pathway regulating muscle stem cell activation and tissue regeneration in resident aged satellite cells), demonstrating that circulating factors modified the function of existing progenitor cells rather than replacing them (196, 197). Translational investigations have also demonstrated that the circulating milieu directly modulates vascular function, such that serum from young animals or humans restored endothelial function and reduced arterial stiffness in aged arteries (198-201). Furthermore, habitual aerobic exercise appears to favorably remodel the circulating milieu, with serum from physically active older adults preserving endothelial function and preventing arterial stiffening to levels comparable with those observed following exposure to serum from young adults (199, 200). Although the precise factor or combination of factors driving these adaptations remains unknown, the currently available evidence supports the concept that tissues communicate through a circulating milieu that integrates endocrine, metabolic, inflammatory, and EV-mediated signaling. Continued investigation into the regulation of this circulating environment is paramount for understanding how peripheral adaptations influence brain health. Accordingly, considering how skeletal muscle and the peripheral vasculature collectively contribute to this circulating milieu is central to describing the muscle–vascular–brain axis.

Skeletal muscle and the peripheral vasculature are interdependent, with adaptations in one system directly influencing the structure and function of the other. This coordinated crosstalk is increasingly recognized as a critical determinant of brain health and resilience to neurodegeneration. The 2024 Lancet Commission estimated that 45% of dementia cases may be preventable through modification of risk factors across the lifespan, and excitingly, many are responsive to interventions targeting skeletal muscle and vascular health (4). While the benefits of exercise are well established for cognition, in large part through vascular pathways (e.g., see the IGNITE study (48, 115)), here we emphasize skeletal muscle as a first-line target with the potential to influence brain health through both vascular-dependent and independent mechanisms.

Traditionally, resistance exercise studies have focused on endpoints of muscular strength and hypertrophy. However, accumulating evidence indicates that improvements in skeletal muscle confer broader systemic benefits that extend to the brain, likely through integrated mechanisms including reductions in inflammation and improvements in mitochondrial and microvascular function (17, 66, 186, 202). Consistent with this perspective, the American Heart Association (AHA) has highlighted that resistance training favorably impacts arterial stiffness, endothelial function, inflammation, sleep, and quality of life (91), all of which are closely linked to ADRDs (5). As noted by the AHA, strength exercise training is associated with favorable structural and functional brain adaptations, including reduced white matter lesion burden and functional changes, ultimately demonstrating the potential to improve cognitive function in individuals with or at risk for ADRDs (121, 122, 203). These observations suggest that resistance training-induced skeletal muscle adaptations support brain health through multiple converging pathways.

As previously described, skeletal muscle also communicates with the brain through endocrine-like signaling mechanisms. Even in the absence of overt exercise, activation of skeletal muscle metabolic pathways can initiate signaling processes that influence the brain. For example, in mice, pharmacological activation of skeletal muscle AMPK using AICAR improved spatial memory and hippocampal gene expression, recapitulating key features of exercise-induced neuroplasticity (204). These effects were abolished in mice lacking skeletal muscle AMPK, demonstrating that muscle-derived signaling is necessary for these adaptations. Furthermore, transcriptomic analyses also showed coordinated upregulation of metabolic pathways in skeletal muscle alongside increased expression of genes related to neuronal development and synaptic plasticity in the hippocampus, strongly supporting a link between peripheral metabolic activation and the CNS. Again, it should be noted that although these signals are muscle-derived, they are largely mediated by circulating myokines and metabolites, underscoring that even “direct” muscle–brain communication depends on a healthy peripheral vascular system.

In response to chronic exercise, skeletal muscle adaptations further enhance the release of anti-inflammatory myokines and promote mitochondrial remodeling (205, 206). These changes may shift microglial phenotype toward a less inflammatory state, reduce astrocyte reactivity, and create a more favorable environment for neuroplasticity (207). Improvements in skeletal muscle function also enhance peripheral vascular health, providing an additional pathway through which muscle adaptations support brain resilience (30). Regarding macrovascular health, recent evidence has shown that muscle strength is inversely associated with arterial stiffness in older women, suggesting that this functional characteristic of skeletal muscle may be protective against vascular aging (208). This is likely, at least in part, due to resistance training's ability to improve endothelial function and reduce blood pressure (91, 208, 209). A previous investigation by the Jenkins laboratory group clearly showed that resistance exercise (9-wk intervention) reduced total peripheral resistance (via repeated shear stress–induced endothelial signaling), facilitating lower arterial pressure (209). Moreover, evidence also shows that skeletal muscle impacts microvascular function, such that individuals with greater muscle mass or metabolic activity often exhibit enhanced microvascular reactivity (210). Reactive hyperemia, a commonly used index of microvascular function (as previously described) (68, 69), may therefore reflect not only vascular responsiveness but also underlying skeletal muscle properties. During transient ischemia, tissue oxygen desaturation reflects the imbalance between oxygen delivery and consumption, creating an ischemic vasodilatory stimulus (i.e., hypoxic insult) that influences the subsequent hyperemic response (68, 71, 211). Across multiple studies, the magnitude of desaturation is strongly associated with the hyperemic response (r = −0.67 to −0.72), suggesting that skeletal muscle metabolism has at least a partial role in this phenomenon (71). This observation challenges the traditional interpretation of reactive hyperemia as a purely vascular measure; rather, it may represent a property of muscle–vascular coupling, in which mitochondrial oxygen consumption and metabolite accumulation (e.g., adenosine, NO intermediates, prostaglandins) drive vascular responses.

Supporting this view, past studies have suggested that the predictive value of reactive hyperemia may be driven more by muscle oxidative capacity than by microvascular function (68, 211, 212). Consistent with this interpretation, we have reported that LST is modestly associated with indices of ischemia-induced desaturation (r = 0.29–0.40) (213, 214), and differences in hyperemic responses across populations may, in part, be explained by variation in metabolically active tissue. However, the contribution of skeletal muscle to reactive hyperemia appears to be context-dependent, as we reported in healthy young adults that differences in oxidative capacity did not consistently translate into differences in hyperemic responses (215), suggesting that muscle metabolism may play a larger role under different conditions (e.g., aging and/or disease). Taken together, these findings suggest that the determinants of reactive hyperemia extend beyond skeletal muscle morphology and oxidative capacity alone. Because skeletal muscle characteristics accounted for only part of the variability in the hyperemic response, while chronological age provided additional explanatory value (213), our findings suggest that biological processes accompanying aging, rather than chronological age itself, likely contributed to the variability in vascular function. Although this study did not identify a specific mechanism, it remains possible that age-related changes in neural function are one such contributing factor, as discussed next.

Declines in skeletal muscle and vascular function may not simply be downstream consequences of neurological disease but may instead precede cognitive impairment (34, 35, 216). These systems are physiologically intertwined, with overlapping trajectories that likely reflect shared pathophysiological mechanisms. Central to this interaction is the motor unit, which integrates neural, muscular, and vascular function (217). Motor unit function depends on adequate microvascular perfusion, mitochondrial capacity, and NMJ integrity, all of which are sensitive to endothelial dysfunction, metabolic dysregulation, and inflammation (218). Peripheral nerves, such as α-motor neurons, rely on the vasa nervorum for oxygen and nutrient delivery, and impairments in limb perfusion are associated with reduced nerve conduction velocity (125). For example, older adults with peripheral artery disease exhibit slower nerve conduction independent of glycemic status, indicating that modest reductions in perfusion can impair neural function (125). In addition, increased sympathetic activity may further compromise neural perfusion through vasoconstriction of these vessels, as demonstrated by reductions in nerve blood flow mediated by α-adrenergic signaling in the vasa nervorum (219). Hotta and others (219) elegantly demonstrated this in rats by showing that electrical stimulation of the lumbar sympathetic trunk produced reductions in nerve blood flow, and that this was largely abolished by α-adrenergic blockade (e.g., phentolamine). Over time, these, along with other factors, may contribute to cycles of denervation and incomplete reinnervation, leading to motor unit loss and muscle atrophy, which may reduce mitochondrial and resting metabolic activity, thereby attenuating the ischemic stimulus and subsequent hyperemic response. Taken together, these findings suggest that skeletal muscle health, mediated in part by preserved motor unit function, plays a role in shaping microvascular function. Motor units may therefore represent an underappreciated contributor to the integrated muscle–vascular mechanisms supporting cardiovascular and brain health.

Clinical evidence further supports this integrated model, as a 12-month randomized trial in older adults with cerebral small-vessel disease and MCI reported a modest between-group difference in cognitive performance favoring progressive resistance training over the control intervention (186). Although within-group improvements were not observed, their findings suggest that resistance training may have attenuated cognitive decline relative to the control group. Resistance training was also associated with reduced circulating CRP, a marker of systemic inflammation linked to vascular dysfunction, mitochondrial health, and BBB integrity. Given that inflammation impairs microvascular function and muscle metabolism, these findings support a role for skeletal muscle–targeted interventions in modulating brain health through integrated systemic pathways. Of note, this study did not evaluate peripheral neuromuscular adaptations to resistance training; however, excitingly, recent robust evidence shows that older adults maintain their ability to improve motor unit characteristics, including motor neurons (118). These data jointly suggest that targeting skeletal muscle elicits a multilevel adaptive response. Enhanced motor unit function improves recruitment, increases metabolic demand, and augments vascular and endocrine signaling. These changes promote endothelial function, reduce inflammation, and increase the release of myokines (likely) implicated in neuroprotection (14, 18, 22). Thus, skeletal muscle is a critical link among the neural, vascular, and metabolic systems, with important implications for promoting resilience (Figure 4).

Figure 4.

This graphic highlights lifestyle-dependent skeletal muscle adaptations and their influence on brain health and resilience. Active and sedentary lifestyles produce distinct skeletal muscle characteristics that may differentially influence brain health across the lifespan. Regular physical activity is associated with adaptations such as enhanced motor neuron excitability and conduction, increased muscle size, strength, power, and endurance, and elevated release of myokines and other signaling factors. These peripheral adaptations support neuronal activity, cognitive function, and resilience to neurodegenerative diseases such as Alzheimer’s Disease and related dementias. In contrast, sedentary lifestyles are associated with reduced neuromuscular function, muscle size, strength, power, and endurance, as well as reduced myokine signaling, which may contribute to neuronal dysfunction, cognitive decline, and reduced resilience. Created in BioRender. Keller, J. (2026) https://BioRender.com/sjtmzbv

Recent clinical trials and emerging nonpharmacological therapies aimed at the promotion of brain health

Historically, trials that focused on single-domain interventions to preserve brain health throughout the lifespan have shown limited efficacy (9). These efforts have now shifted to more holistic, lifestyle-based interventions in recent years, which target multiple domains for the prevention and management of cognitive decline, especially in the context of ADRDs. These approaches are attractive due to their (relatively) low cost, favorable safety outcomes, and scalability. Evidence from randomized clinical trials, such as the FINGER, US POINTER (US Study to Protect Brain Health Through Lifestyle Interventions to Reduce Risk), SMARRT (Systematic Multidomain Alzheimer’s Risk Reduction Trial), and the MIND diet, indicates that multidomain lifestyle interventions can modestly slow cognitive decline, even in at-risk populations. These trials support the concept that targeting modifiable peripheral functions, particularly in skeletal muscle and the vasculature, may preserve brain health. Promising nonpharmacological approaches, including passive heating, HIIT, creatine supplementation, and RIPC, can also support these peripheral systems, potentially encouraging favorable interorgan communication and improving brain health. While most evidence for these interventions is limited to cardiovascular outcomes, given the tight coupling between peripheral vascular health and cerebral perfusion and neurovascular function, these adaptations are hypothesized to translate to improvements in brain health, although direct evidence remains limited.

1. Large-scale clinical trials

The FINGER study is a landmark example of a multidomain intervention comprising a 2-year randomized trial involving over 1,200 at-risk older adults that combined dietary guidance, physical activity, cognitive training, and vascular risk monitoring (12). Compared with the current standard care, the intervention resulted in modest improvements in global cognition (~25% greater relative improvements), with the most consistent benefits observed in executive function and processing speed. Perhaps most notably, participants in the control group were approximately 30% more likely to exhibit cognitive decline over the study period. Although this relative difference appears substantial in isolation, it occurred alongside relatively small between-group differences in cognition and should therefore be interpreted within the context of the overall cognitive effects observed in the trial. The US POINTER trial extended these findings to a larger and more comprehensive cohort (>2,000 participants). Within this trial, both structured and self-guided interventions improved cognitive performance over time; however, the structured program, which included supervised exercise and clinical monitoring, conferred a small additional benefit (187). And consistent with FINGER, improvements were most pronounced in executive function, and effects were greater among individuals with lower baseline cognitive performance, suggesting that those at higher risk garnered the greatest benefit.

Beyond the design of the FINGER and US POINTER trials, the SMARRT represented a change toward precision-based interventions, tailoring multidomain strategies to individual risk profiles. In this smaller trial (n = 172), personalized interventions (i.e., precision prevention strategies) targeting physical activity, sleep, mood, and cardiometabolic health produced modest improvements in cognitive performance, slightly greater than those observed in prior multidomain trials (220). This evidence suggests that individualized approaches may enhance efficacy, although larger studies are needed to confirm this advantage. Furthermore, dietary approaches have been explored as a potential means of preventing or delaying the onset of neurodegeneration. The most prominent diet-focused investigation was the MIND trial, which involved approximately 600 participants (13). Of note, both the intervention and control groups received dietary counseling and achieved similar weight loss (~5 kg), resulting in comparable improvements in cognition. These results demonstrate that general lifestyle improvements, like weight loss and reduced inflammatory burden, may be more influential than specific dietary patterns alone. However, it remains possible that specific dietary strategies may still contribute meaningfully when combined with other interventions.

2. Emerging nonpharmacological therapies

Passive Heating.

Passive heating has emerged as a promising strategy to improve vascular function and, by extension, brain health. There are various options for delivering this therapy, such as sauna, whole-body water immersion, or localized limb heating, each of which acts as an acute stressor that elicits local and systemic cardiovascular responses. Epidemiological data indicate that frequent sauna use is associated with a reduced risk of ADRDs over long-term follow-up (221). Mechanistically, heat stress increases cardiac output (primarily via increased heart rate) and redistributes blood flow toward the skin and skeletal muscle, thereby generating shear stress that can promote vascular adaptation. Repeated exposure improves endothelial function (e.g., flow-mediated dilation [FMD]), microvascular reactivity, and arterial stiffness within weeks (49). As previously described, improvements in peripheral vascular health (e.g., arterial stiffness) remain particularly relevant for cerebrovascular health (38, 39, 41, 77, 78). Moreover, these adaptations appear to be driven in large part by shear stress–mediated signaling, as experimentally blunting shear stress prevents improvements in endothelial function (222). Passive heating also induces the release of circulating factors, including heat shock proteins (HSP) and IL-6, which contribute to cytoprotection and interorgan communication (223, 224). These HSPs support endothelial integrity and NO signaling, while IL-6 may act as a systemic signal linking peripheral stress to central adaptations. For instance, in endothelial cells, suppression of HSP70 signaling increases apoptosis and impairs NO-related pathways (225). Beyond their intracellular roles, HSPs may also encourage interorgan communication, as circulating HSPs have been reported to originate from multiple tissues, including the brain itself (224, 226), supporting bidirectional signaling between the brain and peripheral tissues. To be clear, direct effects on cognitive function and long-term brain health remain incompletely understood, although epidemiological evidence linking frequent sauna use with reduced ADRD risk and the mechanistic evidence described above support passive heating as a promising strategy deserving further investigation.

High-intensity interval training.

We previously mentioned this form of exercise, which is characterized by repeated bouts of high-intensity exercise interspersed with recovery periods, resulting in large fluctuations in metabolic demand and blood flow (227). These rapid perturbations drive dynamic changes in shear stress and vascular signaling, both in the periphery and within the cerebrovasculature. While acute increases in shear stress are greater than those observed during moderate-intensity exercise, long-term cerebrovascular adaptations appear to depend more on repeated exposure than on stimulus magnitude alone. HIIT is also a potent stimulus for BDNF release, a key mediator of neuroplasticity (as previously described). Interestingly, the BDNF response appears to be intensity-dependent in some contexts and closely linked to metabolism (e.g., lactate), particularly during endurance-based exercise, suggesting that peripheral metabolic perturbations drive downstream neurotrophic signaling, positioning HIIT as an attractive exercise-focused nonpharmacological therapy (228). Again, it is important to consider that the brain itself contributes substantially to circulating BDNF during exercise, supporting a bidirectional signaling network between central and peripheral systems (14, 18-20). In addition to its neural effects, HIIT improves endothelial function and may produce greater vascular adaptations than moderate continuous exercise in certain at-risk clinical populations. These findings support the peripheral vasculature as a central integrator of HIIT-induced signals, linking skeletal muscle metabolism, vascular function, and brain health. Perhaps most importantly, HIIT may be one of the most time-efficient and efficacious approaches to promote brain health, given compelling evidence shows that even low-frequency (e.g., once a week) participation can confer cardiovascular benefits (51).

Creatine supplementation.

Creatine monohydrate is one of the most widely studied supplements/ergogenic aids, with established roles in cellular energy metabolism, specifically in the context of sport and human performance. By buffering ATP availability through the phosphocreatine system, creatine supplementation supports both skeletal muscle and neural function, including mitochondrial capacity and synaptic transmission (229). Emerging evidence suggests that creatine may also influence vascular function, with pilot studies demonstrating improvements in endothelial function and microvascular responsiveness following supplementation (230). For example, short-term creatine supplementation can increase FMD and enhance muscle oxygen resaturation after ischemia, suggesting improvements in both conduit artery and microvascular function (230). These adaptations may enhance oxygen delivery and cellular energetics in both muscle and neuronal tissue. At least in part due to this potential, the Creatine to Augment Bioenergetics in AD (CABA) study at the University of Kansas AD Research Center was developed and has preliminarily shown that creatine supplementation may modestly increase strength in individuals with AD. However, to date, the CABA study has not demonstrated observable benefits in cognition or broader neuromuscular outcomes (52, 231). Overall, while evidence supporting creatine’s role in skeletal muscle bioenergetics is robust, data demonstrating improvements in cognition or broader brain health remain preliminary despite encouraging mechanistic findings (e.g., vascular responses) and therefore require confirmation from larger clinical trials.

Remote ischemic preconditioning (RIPC).

This protocol involves repeated cycles of limb ischemia and reperfusion while at rest and was originally developed as a cardioprotective intervention. More recently, it has been explored as a chronic therapy that can induce systemic adaptations. Preclinical studies demonstrate that RIPC enhances cerebral blood flow, vascular remodeling, and cognitive function (232), and in humans, chronic RIPC has been shown to reduce stroke recurrence and improve cerebral perfusion in patients with vascular disease (233). Relevantly, RIPC also improves peripheral vascular function, with increases in endothelial function observed in both treated and untreated limbs, suggesting systemic effects (234). These adaptations appear to be mediated by circulating factors, as protective effects can be transferred to RIPC-naïve tissue through plasma and EVs ex vivo and even across species (50, 235). These findings support the notion that RIPC may act through interorgan communication involving both neural and humoral signaling pathways (235).

Although RIPC is typically performed independently of exercise, cyclical blood flow restriction (BFR) exercise is a conceptually related method, as both models involve repeated episodes of limb ischemia and reperfusion (236). When BFR is applied in a cyclical manner to incorporate repeated episodes of ischemia and reperfusion, it elicits comparable cerebrovascular responses without increasing arterial pressure compared with conventional exercise, despite evidence of altered sympathetic activation (237, 238). While these findings suggest that cyclical BFR may engage physiological pathways that overlap with those of RIPC, current evidence is limited to acute studies, and it remains unknown whether BFR training promotes greater cognitive resilience via interorgan signaling than traditional free-flow exercise. Future studies should determine the optimal dosage of ischemia–reperfusion applications, including the frequency, intensity (i.e., occlusion pressure), time (duration), and type (RIPC vs. BFR exercise), to establish an evidence-based FITT framework that optimizes the hypothesized benefits.

Future directions and conclusion

Recent large-scale analyses of amyloid-beta–targeting monoclonal antibodies highlight a critical limitation in current pharmaceutical therapeutic approaches for AD (11). Despite targeting a central pathological hallmark, these interventions produce only trivial or clinically negligible effects on cognition and functional outcomes, while increasing the risk of adverse side effects like amyloid-related imaging abnormalities (i.e., ARIA) (11). Across thousands of participants, improvements in cognitive and dementia severity measures are small and often indistinguishable from no effect, reinforcing the need to reconsider approaches that focus narrowly on late-stage neuropathology (11). Clearly, this underscores a fundamental challenge, such that by the time overt neurodegeneration is apparent, disease processes may be too advanced for meaningful reversal with our currently available tools. Therefore, continued emphasis must be placed on system-based preventive strategies that promote favorable interorgan communication and resilience rather than on disease reversal. As described throughout this review, the skeletal muscle and peripheral vasculature systems are pivotal, modifiable contributors to brain health, via their (in)direct roles in cerebral perfusion, neurovascular coupling, BBB integrity, and inflammatory load.

In addition to non-specific interventions for these systems, future work should prioritize developing precision-based preventive trials that account for individual variability in genetic, physiological, and sociocultural factors. One potentially fruitful line of research is to examine the modifying role of genotypes (e.g., APOE-ε4 carriage) on responses to exercise and other interventions across at-risk populations. At the same time, broader determinants of health, including environmental exposures, psychosocial stress, and structural inequities, known as the neural exosome (239), must be integrated into models of neurodegenerative risk, as these factors profoundly influence vascular health and brain outcomes. Along these lines, a potential next step could be to better delineate the pathways linking skeletal muscle, vascular function, and the brain, as the relative contributions of muscle mass, excitability, metabolic stress, and exercise modality to the release of myokines, exerkines, and EVs remain incompletely understood. Disentangling these factors will be essential for optimizing intervention strategies and maximizing their neuroprotective effects. Lastly, expanding the use of accessible peripheral biomarkers represents a key opportunity for early detection and risk stratification. Measures of microvascular function (e.g., PAT), arterial stiffness, and neuromuscular function (e.g., conduction velocity) may serve as scalable peripheral biomarkers to identify individuals at risk before the onset of cognitive decline. It must be emphasized that improving access to these tools and associated clinical trials is essential to ensure equitable translation of these advances.

In conclusion, brain health is not determined exclusively within the CNS but instead reflects the integrated health of multiple peripheral organs, particularly skeletal muscle and the vasculature. Dysfunction in either system may contribute to cognitive decline; however, previous studies suggest that peripheral impairments often precede overt cognitive symptoms. Thus, these measurable impairments may serve as useful harbingers for earlier intervention. Accordingly, promoting timely and accessible interventions for all people is paramount to improving the current trajectory and prevalence of neurodegenerative diseases.