Insulin Resistance’s Impact on Cognition in Middle Aged Adults from the PREVENT cohort: Interactive Effects with Depression

Background Alzheimer’s disease, type 2 diabetes mellitus, and depression are significant challenges facing public health. Research has demonstrated common comorbidities amongst these three conditions, typically focusing on two of them at a time. Objectives The goal of this study, however, was to assess the interrelationships between the three conditions, focusing on mid-life risk before the emergence of dementia caused by Alzheimer’s Disease. Methods In the current study, we used data from 665 participants from the prospective cohort study, PREVENT. Findings Using structural equation modelling, we showed that (i) insulin resistance predicts executive dysfunction in older but not younger adults in midlife, that (ii) insulin resistance predicts self-reported depression in both older and younger middle-aged adults, and that (iii) depression predicts deficits in visuospatial memory in older but not younger adults in midlife. Conclusions Together, we demonstrate the interrelations between three common non-communicable diseases in middle-aged adults. Clinical Implications We emphasise the need for combined interventions and the utilisation of resources to help adults in midlife to modify risk factors for cognitive impairment, such as depression and diabetes. Funding The PREVENT study was funded by the Alzheimer’s Society (grant numbers 178 and 264), the Alzheimer’s Association (grant number TriBEKa-17-519007) and philanthropic donations. GR acknowledges funding for this work for his research programme funded by the Medical Research council (Dementias Platform UK) and Five Lives Ltd. IK declares funding for this project through Medical Research Council (Dementias Platform UK), NIHR Oxford Health Biomedical Research Centre and NIHR personal awards. SG acknowledges funding for salary from the Medical Research Council Nutrition Research Partnership Collaboration Award (MR/T001852/1). What is already known on this topic Mood disorders and metabolic diseases are known to be frequently comorbid. Furthermore, both conditions are known to be associated with cognitive impairment and cognitive decline. There has been some evidence that the risk of cognitive impairment associated with diabetes and depression is most notable in midlife. However, studies focusing on this period of life have been sparse and most research has modelled bivariate correlations amongst cognitive impairment, depression, and diabetes. As such, this study was conducted in order to model the interrelations between the three conditions in a large cohort, whilst focusing on midlife as depression and diabetes in this period are thought to carry higher risk for cognitive impairment. What this study adds Whilst insulin resistance, as a core feature of diabetes, was related to depression across all stages of midlife, the relationship with cognitive functioning was more complex. In the current study, we found that the stage of midlife in which middle-aged adults find themselves moderates the relationship between insulin resistance and cognition and depression and cognition. That is, only in older middle aged adults does insulin resistance predict impaired cognition (i.e., executive function) and does depression predict impaired cognition (i.e., visuospatial memory). How this study might affect research, practice or policy Clinicians should be mindful of the impact of comorbidities between cognitive impairment, metabolic diseases, such as diabetes, and mood disorders, such as depression in midlife. Given the risk of intractable dementia in individuals with cognitive impairment, available resources for intervening in modifiable risk factors, such as depression and diabetes, should be considered for adults in the middle period of life. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The PREVENT study was funded by the Alzheimer's Society (grant numbers 178 and 264), the Alzheimer's Association (grant number TriBEKa-17-519007) and philanthropic donations. GR acknowledges funding for this work for his research programme funded by the Medical Research council (Dementias Platform UK) and Five Lives Ltd. IK declares funding for this project through Medical Research Council (Dementias Platform UK), NIHR Oxford Health Biomedical Research Centre and NIHR personal awards. SG acknowledges funding for salary from the Medical Research Council Nutrition Research Partnership Collaboration Award (MR/T001852/1). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used ONLY openly available human data that were originally located in the prospective PREVENT cohort. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors