Review of Associations of Diabetes and Insulin Resistance With Brain Health in Three Harmonised Cohort Studies of Ageing and Dementia

Diabetes increases the risk of dementia, and insulin resistance (IR) has emerged as a potential unifying feature. Here, we review published findings over the past 2 decades on the relation of diabetes and IR to brain health, including those related to cognition and neuropathology, in the Religious Orders Study, the Rush Memory and Aging Project, and the Minority Aging Research Study (ROS/MAP/MARS), three harmonised cohort studies of ageing and dementia at the Rush Alzheimer's Disease Center (RADC). A wide range of participant data, including information on medical conditions such as diabetes and neuropsychological tests, as well as other clinical and laboratory-based data collected annually. Neuropathology data are collected in participants who agree to autopsy at death. Recent studies have measured additional peripheral and brain IR data, including multi-omics. This review summarises findings from the RADC cohort studies that investigate the relation of diabetes and IR in older adults to cognition, neuropathology, omics in dementia, and other brain health measures. Examining the risk of clinically diagnosed dementia in older adults, our study found a 65% increased risk of Alzheimer's disease (AD) dementia in individuals with diabetes compared with those without. Regarding cognitive function, we have consistently observed associations of diabetes, as well as both peripheral and brain IR, with worse and declining performance in global cognition and specific cognitive domains, particularly semantic memory and perceptual speed. Studies utilising neuropathological data showed associations of diabetes and peripheral IR with brain infarcts, while brain IR measures, notably alpha serine/threonine-protein kinase1 (AKT1), were associated with both brain infarcts and AD pathology. Multi-omics studies suggested shared causal genes and pathways between diabetes and dementia. Recent epigenetic studies have revealed associations between IR and AD risk, along with distinct 5-hydroxymethylcytosine signatures in diabetes-associated AD. Furthermore, our studies have utilised other available data to investigate the impact of diabetes on neurological outcomes other than cognition and reported worsening of parkinsonian-like signs in diabetes. Recent studies have also explored risk factors for diabetes and have reported associations between lower literacy and decision-making abilities with elevated haemoglobin A1C levels, a peripheral IR measure. Overall, our findings, as summarised in this review, illustrate a range of mechanistic and other insights into the complex relationship of diabetes and IR with brain health. These findings may have important implications for future research on the ageing brain, including the prevention of cognitive decline and dementia in persons at risk for or with diabetes.