BackgroundAlzheimer’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.ObjectiveThe 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.MethodsIn the current study, we used cross-sectional data from 665 participants from the cohort study, PREVENT.FindingsUsing 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.ConclusionsTogether, we demonstrate the inter-relations between three common non-communicable diseases in middle-aged adults.Clinical implicationsWe 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.