Climate Change and Non-Communicable Disease Multimorbidity: An Adverse Outcome Network Framework Linking Metabolic, Cardiovascular, and Neurodegenerative Pathways

Background: Climate change intensifies human exposure to heat stress, air pollution, wildfire smoke, altered dietary patterns, water quality degradation, psychosocial stress, and disrupted circadian rhythms. Epidemiological evidence links these exposures to rising incidence of non-communicable diseases (NCDs), including type 2 diabetes mellitus (T2D), atherosclerotic cardiovascular disease (CVD), and neurodegenerative disorders such as Alzheimer’s disease (AD) and vascular dementia (VaD). However, the mechanistic pathways connecting climate-driven stressors to NCD multimorbidity remain fragmented across disciplines, hindering integrated risk assessment and policy responses.Objectives: This review constructs a mechanistically grounded Adverse Outcome Network (AON) that maps the causal biological architecture from climate-sensitive molecular initiating events (MIEs) through shared key events (KEs) to the adverse outcomes of T2D, CVD, and neurodegeneration. The AON is developed in accordance with OECD Adverse Outcome Pathway (AOP) principles, embeds climate change as an exposome-level meta-driver, and is designed to support quantitative AOP (qAOP) modelling and lifecycle vulnerability analysis.Methods: We synthesised evidence from environmental health, molecular toxicology, systems biology, climate science, and clinical epidemiology to identify MIEs across nine climate-sensitive exposure domains, seventeen KEs, and their key event relationships (KERs). Each element was evaluated using established weight-of-evidence criteria (biological plausibility, empirical support, essentiality) with climate-specific uncertainty quantification. Shared hub KEs were identified through network topology analysis, and lifecycle windows of susceptibility were mapped to the AON architecture.Results: The AON reveals that climate-sensitive stressors converge on a compact set of hub KEs—chronic low-grade inflammation, oxidative stress and mitochondrial dysfunction, insulin resistance, endothelial dysfunction, NLRP3 inflammasome activation, and blood–brain barrier disruption—that serve as mechanistic amplifiers across all three disease domains. Seven branching causal pathways connect climate stressors (heat, PM2.5/ozone, wildfire smoke, allergens, extreme weather, water salinity, and microplastics) through these hubs to the three adverse outcomes. Six reinforcing feedback loops create tipping-point dynamics that explain the non-linear, accelerating trajectories of NCD multimorbidity under climate stress. Lifecycle vulnerability analysis identifies prenatal programming, midlife metabolic syndrome, and late-life physiological reserve depletion as critical windows. Sub-pathways with the highest quantitative tractability for qAOP development are identified, alongside a hybrid modelling framework integrating PBPK–PD, Bayesian hierarchical models, and mechanistic digital twin approaches.Conclusions: The AON framework provides a structured, mechanistically transparent tool for climate-health risk assessment. By identifying shared hub KEs as high-leverage intervention targets and mapping them to translational early warning systems, it supports the development of integrated prevention strategies that address NCD multimorbidity as a systemic consequence of environmental change. The framework is directly applicable to regulatory risk assessment under REACH and EFSA mandates, to New Approach Methodologies (NAMs) and Safe and Sustainable by Design (SSbD) contexts, and to climate adaptation planning