Abstract. Given the very limited success in Alzheimer’s disease (AD) drug development over the past decades an extended search for therapy beyond the amyloid-b and tau hypotheses is needed. According to one promising and underexplored hypothesis, in AD the key pathophysiological events are linked with brain insulin resistance. This hypothesis, referred to as Type 3 Diabetes (T3D), is supported by many lines of evidence including altered insulin pathways in AD brains and cognitive benefits of anti-diabetic drugs. The mechanisms of T3D pathogenesis remain unknown, however. Extensive research demonstrated that suppression of different nodes in the growth hormone (GH)/ insulin-like growth factor (IGF)/ mechanistic target of the rapamycin (mTOR) cascade slows down aging and aging-associated cognitive decline in a range of model organisms. Insulin and IGF hormonal cascades have a common ancestry and the two axes of hormonal signaling are not fully separated. Their negative feedback loops overlap, so that activation of IGF-1 receptor (IGF1R) results in suppression of insulin receptor substrate (IRS) a key node in insulin signaling. Following this evidence, we hypothesize that chronic activation of a molecular cascade downstream of IGF1 results in a negative feedback suppression of insulin signaling (Fig. 1) in the brain and T3D development. Additionally, IGF1R negatively regulates autophagy and positively regulates NF-kB-mediated inflammation providing bridges between T3D, misfolded proteins, and inflammatory mechanisms of AD and AD-related dementias (ADRD). Informed by this hypothesis, we have conducted preliminary proof of a principle longevity experiments with mice in which small molecule IGF1R inhibitors orally administered starting 13 months of age (~45 human years) prevented the decline of short-term memory, prevented the development of insulin resistance, improved grip strength, decreased frailty, and increased lifespan. Capitalizing on these results the current proposal will allow us to make further steps toward the development of AD therapy based on IGF1R inhibition via the following aims: (1) to optimize drug-candidate molecules via computational modeling and subsequent testing of their target affinity and selectivity, toxicity properties, absorption, distribution, metabolism, and excretion characteristics; and (2) to characterize neurodegeneration prevention by optimized molecules using two mouse models: wildtype mice naturally developing cognitive decline with age and 3xTg-AD mouse model of AD. The ability of optimized drugs to improve cognitive function and improve markers of insulin signaling, autophagy, inflammation, Aβ, and tau pathology in their brains will be analyzed. This project will result in a candidate drug(s) for AD and ADRD, targeting novel molecular mechanisms and ready for preclinical development.