Abstract
(1) Background: Insulin resistance (IR) is increasingly recognized not only as a key factor in metabolic and cardiovascular disorders but also as an important contributor to cognitive decline. The growing prevalence of obesity, type 2 diabetes mellitus, and cardiovascular disease (CVD), paralleled by rising rates of dementia, highlights the need for an integrative model linking these conditions. The emerging cardio-metabolic-brain axis proposes a unified model explaining how biomarkers of metabolic stress, adipose-tissue-derived mediators, and abnormalities in laboratory parameters interact with vascular injury and neurodegeneration. (2) Methods: A comprehensive literature review was conducted using MEDLINE, SCOPUS, and Web of Science databases, complemented by additional searches in Embase and Cochrane Library. Studies from the past decade were screened using keywords such as "insulin resistance", "cardio-metabolic-brain axis", "cognitive decline", and "cardiovascular disease". Both epidemiological and mechanistic studies were analyzed to summarize current evidence and identify research gaps. (3) Results and Conclusions: Evidence indicates that insulin resistance contributes to endothelial dysfunction, chronic inflammation, and oxidative stress, driving the metabolic abnormalities characteristic of obesity and type 2 diabetes and promoting both atherosclerosis and neurodegeneration. Individuals with elevated IR-regardless of diabetes status-display higher risks of cardiovascular events and measurable cognitive decline. Brain insulin resistance further impairs glucose utilization, disrupts synaptic function, and facilitates amyloid accumulation, reflecting mechanisms observed in Alzheimer's disease. These findings support IR as a key biomarker linking metabolic stress, vascular injury, and neural vulnerability within the cardio-metabolic-brain axis. Early identification of IR, together with targeted lifestyle and pharmacological interventions, may therefore offer dual benefits for cardiovascular and brain health. Continued longitudinal research is needed to validate this integrative model and refine therapeutic strategies aimed at improving insulin sensitivity.