From Limb to Brain: Lymphedema as a Systemic Disease with Metabolic, Immunological, and Neurodegenerative Consequences and the Disease-Modifying Potential of Lymphaticovenous Anastomosis—An Integrative Analysis

Abstract Lymphedema has traditionally been viewed as a localized disorder characterized by regional fluid accumulation and tissue swelling. However, emerging evidence challenges this paradigm, revealing that lower limb lymphedema induces significant systemic pathophysiological changes. This review synthesizes recent findings demonstrating that lymphedema triggers widespread oxidative stress, chronic inflammation, dysregulated gene expression in circulating monocytes, and contralateral limb muscle edema—even in the absence of clinical lymphedema in the unaffected limb. Furthermore, we examine the potential association between lymphedema and increased Alzheimer's disease (AD) risk through shared mechanisms involving oxidative stress and neuroinflammation. Lymphaticovenous anastomosis (LVA), a minimally invasive supermicrosurgical technique, has emerged as an effective intervention that not only reduces limb volume but also reverses many of these systemic alterations. Studies utilizing advanced imaging techniques, including magnetic resonance volumetry and diffusion tensor imaging, combined with comprehensive biomarker analyses, have documented post-LVA improvements in antioxidant capacity, reduction in oxidative stress markers, normalization of inflammatory cytokines, recovery of dysregulated gene expression patterns, and decreased muscle edema bilaterally. Additionally, preliminary data suggest LVA may reduce AD biomarkers, including tau protein and amyloid-beta levels, while increasing neuroprotective factors such as brain-derived neurotrophic factor. These findings fundamentally redefine lymphedema as a systemic condition with far-reaching metabolic and potentially neurodegenerative consequences, positioning LVA as a therapeutic intervention with benefits extending beyond local symptom control to systemic disease modification.