PROJECT SUMMARY Nearly 25% of Americans aged 65 and older have Type-2 diabetes mellitus (T2DM) and more than half have elevated hemoglobin A1c indicating impaired glucose tolerance, or prediabetes. T2DM can affect the brain through neuronal toxicity of hyper- and hypoglycemia episodes, microvascular insults, impaired glucose transfer and insulin resistance. The neurologic impact of T2DM is widespread and can lead to structural, functional, and metabolic brain changes. Clinically, T2DM is associated with faster cognitive decline and a higher risk of dementia, including Alzheimer’s disease (AD). The link between T2DM-associate brain changes and cognitive decline is not completely understood, resulting in a paucity of targets for therapeutic intervention. One potential target is cortical plasticity itself, the mechanisms of which can be assessed in vivo in humans using transcranial magnetic stimulation (TMS). This approach uses single-pulse TMS to index cortical excitability and a form repetitive TMS called intermittent theta-burst stimulation (iTBS) to induce NMDA- receptor dependent changes in cortical excitability that resemble the synaptic mechanisms of long-term potentiation (LTP) plasticity. In a previous NIH-funded study (R21 NS082870), which serves as the foundation for the current proposal, we used this TMS-iTBS approach to show that older adults with T2DM had reduced LTP-like plasticity compared to healthy controls. Moreover, plasticity in T2DM patients was associated with both cognition and cortical glutamate metabolism as assessed by magnetic resonance spectroscopy (MRS). We performed these TMS and MRS assessments in the motor cortex (M1) using electromyography to record the output of TMS as a motor evoked potential (MEP). The current study seeks to extend these findings to brain regions more directly involved in cognition, including the dorsolateral prefrontal cortex (DLPFC) and inferior parietal lobule (IPL). We will combine TMS with electroencephalography (EEG) and use the TMS- evoked EEG potential (TEP) to index cortical excitability and its modulation by iTBS. Our pilot data supports this approach by showing that iTBS to M1 induces correlated changes in MEPs and TEPs and that the iTBS- induced modulation of TEPs in DLPFC and IPL are associated with tests of executive function and memory, respectively. Our hypothesis is that cognitive dysfunction in T2DM is associated with abnormal glutamatergic neurotransmission, which can be assessed using TMS and MRS. We will perform these assessments in non- demented older patients with T2DM and demographically similar non-diabetic participants, divided into healthy and prediabetic subgroups on the basis of A1c levels. We will collect structural magnetic resonance imaging (MRI) measures of cortical atrophy and comprehensive neuropsychological testing, plus data on known AD risk factors, such as apolipoprotein-E4 status and plasma amyloid-beta levels. If successful, this study will identify neurop...