Alzheimer's disease (AD) is the most common cause of cognitive impairment, but diseases of cerebral blood vessels, particularly the small blood vessels that supply all cells of the brain, are also major contributors. No effective therapies exist, and innovative approaches are needed. The proposed study introduces two conceptual innovations to identify novel therapeutic strategies. First, the study focuses on cerebral small vessel ischemic disease (SVID) induced by dyshomeostasis of amylin, an endocrine hormone that participates in the central regulation of satiety and also known to form pancreatic amyloid in patients with type-2 diabetes. Recent empirical findings advanced in part by our group suggest that axonal degeneration and maladaptation of small vessels, such as gliosis, are linked by vascular deposits of amylin. Our preliminary data also show that amylin deposition in brain capillaries correlates with accumulation of amylin in red blood cells. Working in non-AD rats, we showed that pancreatic expression of human amylin (rat amylin is non-amyloidogenic) promotes vascular amylin deposition leading to microhemorrhages, axonal degeneration and late-life onset neurological deficits. Second, the study introduces a new paradigm that amylin dyshomeostasis modulates brain amyloid composition. Several laboratories (including ours) report the presence of mixed amylin-β amyloid (Aβ) plaques in brains of individuals with pathological AD. To study the amylin-Aβ interaction in vivo, we crossed AD rats with human amylin- expressing rats. Our preliminary data indicate that human amylin-expressing AD rats have accelerated aging and behavioral changes, whereas genetic or pharmacological suppression of amylin is protective. Here, we propose to test these hypotheses by using red blood cell lysates, cerebrospinal fluid samples and clinical data from the MarkVCID study, along with mechanistic studies and amylin-centric therapeutic interventions in rat models of amylin dyshomeostasis-related dementia. Data derived from the proposed specific aims can directly lead to human clinical translational studies for the prevention and treatment of vascular cognitive impairment and/or mixed pathologic disease states that currently lack effective treatments.