COMMETS- Combination MCI Metabolic Syndrome

The investigators propose a proof of concept RCT (randomized clinical trial), testing the efficacy of intranasal insulin (INI) with semaglutide, a combination therapy with strong biological plausibility to benefit impaired cognition through vascular mechanisms, in older adults with MetS (metabolic syndrome) and MCI (Mild Cognitive Impairment), who are enriched for cerebrovascular disease and at high dementia risk. The study will focus on cognitive and biological outcomes, allowing identification of relevant mechanisms.

The Specific Aims of the study are: Aim 1. To examine the ease and precision of use of the intranasal device and once daily semaglutide pill. Aim 2. To examine the adherence to the two types of treatment. Aim 3. To examine the safety profile of the combination of intranasal insulin with semaglutide. The safety profile of each has been published broadly, but the safety of their combination has not been examined. Aim 4. Although the primary goal of the pilot study is proof of concept essential to design a large combination therapy RCT, The investigators will compare the combination of intranasal insulin and semaglutide with the other three groups on a) cognition, b) cerebral blood flow (via ASL MRI), c) glucose uptake (via FDG PET), ADRD(Alzheimer's disease and related disorders)-related blood biomarkers (Aβ42/Aβ40 ratio, pTau181 and 231, NfL and GFAP), and expression of insulin signaling genes from brain derived exosomes.