Amylin is a gut-brain axis hormone, which readily crosses the blood brain barrier (BBB) and mediates activities including regulating glucose metabolism, relaxing cerebrovascular structure and modulating inflammation, all of which could be beneficial for Alzheimer?s disease (AD). Recent studies have shown that mild cognitive impairment (amnestic MCI) and AD patients have a lower concentration of amylin in plasma than the elderly who had normal cognition. In cross-sectional analyses, higher concentrations of plasma amylin are related to better cognitive function, especially in memory and executive domains. Using AD mouse models, our recent study demonstrates that intraperitoneal injection (i.p) of amylin improves learning and memory as well as reduces indices of AD pathology in the brain. Although these studies suggest that exogenous administration of amylin type peptides may be beneficial for AD, amylin can also form amyloid in the pancreas of type 2 diabetes and in the cerebrovasculature of AD brain that may lead to worsened cognition. Thus, it is important and critical to study the longitudinal relationship between the baseline concentration of plasma amylin and cognitive decline during aging process. From the Framingham Heart Study Offspring and Omni Generation 1 cohorts, we propose using plasma samples collected from 1995- 1998 to relate to incident change in cognition and brain structure up to 15 years later. We posit that high levels of plasma amylin are protective for cognitive decline and brain atrophy in aging process. We have five specific aims including 1) studying the distribution of plasma amylin in FHS community based population; 2) determining the relationship between baseline plasma amylin and cognitive changes, including incident mild cognitive impairment and dementia; 3) examining the association between plasma amylin and changes in brain morphology; 4) stratifying these analyses by the presence of ApoE4 allele, diabetes and other vascular diseases and 5) studying the relationship between amylin, A?, lipids, other gut-brain axis peptides and inflammation in FHS. Pramlintide is an amylin analog and an FDA approved drug for diabetes with a favorable safety profile in clinical use. Should we find that high levels of plasma amylin are protective for the incidence of AD, our study will provide additional rationale for a large phase 2 or 3 trial with pramlintide to determine if amylin type peptides can prevent and treat AD. We anticipate that this study may help open a new and unconventional avenue for the therapeutic of AD.