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Background Alzheimer’s disease (AD), type 2 diabetes mellitus (characterised by insulin resistance) and depression are significant challenges facing public health. Research has demonstrated common comorbidities among these three conditions, typically focusing on two of them at a time.Objective The goal of this study, however, was to assess the inter-relationships between the three conditions, focusing on mid-life (defined as age 40–59) risk before the emergence of dementia caused by AD.Methods In the current study, we used cross-sectional data from 665 participants from the cohort study, PREVENT.Findings Using structural equation modelling, we showed that (1) insulin resistance predicts executive dysfunction in older but not younger adults in mid-life, that (2) insulin resistance predicts self-reported depression in both older and younger middle-aged adults and that (3) depression predicts deficits in visuospatial memory in older but not younger adults in mid-life.Conclusions Together, we demonstrate the inter-relations between three common non-communicable diseases in middle-aged adults.Clinical implications We emphasise the need for combined interventions and the use of resources to help adults in mid-life to modify risk factors for cognitive impairment, such as depression and diabetes.