Pathophysiological mechanisms linking osteoarthritis and neurodegenerative disease risk

This review aims to assess the existing evidence that connects osteoarthritis (OA) with neurodegenerative diseases, specifically Alzheimer's disease (AD) and Parkinson's disease (PD), and to elucidate shared mechanisms that may contribute to the development of innovative therapeutic approaches.

We present a narrative review of prior epidemiological, genetic, and mechanistic studies that describe overlapping risk factors and convergent pathological pathways linking OA and neurodegenerative diseases. Key focus areas include metabolic and hormonal influences, inflammatory cytokine signaling, and mitochondrial dysfunction that arise in both OA and neurodegenerative diseases.

Emerging evidence indicates that OA and neurodegenerative diseases share core drivers-advanced age, obesity, metabolic syndrome, and genetic susceptibility. Central to both are chronic inflammation, mediated by tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β), as well as mitochondrial dysfunction, which promote both cartilage degradation and neuronal death. Genetic data reveal consistent activation of NF-κB and JAK/STAT signaling, with contributions from MAPK, TGF-β, and WNT signaling pathways. Preclinical models demonstrate that OA-induced peripheral inflammation can amplify neuroinflammation and accelerate AD-like pathology, underscoring a potential bidirectional link. Despite these associations, causal relationships have not been concretely established.

OA may contribute to neurodegenerative risk through shared inflammatory and metabolic mechanisms, representing an underrecognized intersection between musculoskeletal and neurological diseases. Targeting these convergent pathways offers a promising avenue for dual-purpose interventions. Establishing causality through longitudinal and mechanistic studies could enable early identification of at-risk patients and guide the development of therapies that mitigate both joint degeneration and neurodegeneration.