The Amylin Dyshomeostasis Hypothesis of Vascular Contributions to Cognitive Impairment and Dementia (VCID)

White matter disease is associated with small vessel ischemic disease (VSID) and early pathological processes in many types of dementia. A major scientific question is whether factors that affect viability and functionality of peripheral capillaries can initiate pathological processes in the central nervous system leading to white matter disease. Recent empirical findings advanced in part by our group suggest that in the late onset form of Alzheimer’s disease (AD), white matter rarefaction and pathological maladaptation of small vessels, such as reactive responses of glial cells (gliosis), are linked by vascular deposits of amylin, a pancreatic hormone that is co-secreted with insulin and forms the pancreatic amyloid in patients with type-2 diabetes. Several laboratories report the presence of amylin deposits in the retinal capillaries, the grey matter, and arterial walls of AD patients without diabetes. Our new preliminary data show that inducing “human” amylin dyshomeostasis in normal rats and in AD rats dramatically accelerates aging and leads to vestibulomotor dysfunction, gait abnormalities and increased mortality. Amylin dyshomeostasis promotes amylin accumulation in capillaries and red blood cells (RBCs), which increases RBC to endothelial cell adherence, decreases RBC hemoglobin, and activates hypoxia-inducible factors in endothelial cells leading to arginase-nitric oxide dysregulation. Upregulation of epoxyeicosatrienoic acids, which are lipid mediators formed by endothelial cells, mitigates capillary amylin deposition in brains of human amylin-expressing rats. Based on these preliminary data, we hypothesize that amylin dyshomeostasis in the periphery 1) is an early risk factor of cerebral small vessel disease and mixed amyloid beta-amylin pathology, 2) impairs capillary function and oxygen-carrying capacity of RBCs that can initiate pathological processes in brain aging, and 3) can be mitigated/reversed by activating protective pathways upstream of the interaction of amylin with the capillary-RBC interface. Here, we propose to test these hypotheses by using RBCs, CSF samples and clinical data collected from the MarkVCID cohort for the study of vascular contributions to cognitive impairment and dementia along with mechanistic amylin-centric therapeutic interventions in rat models of amylin dyshomeostasis-related dementia. These studies will provide definitive new knowledge to support (or refute) a novel pathway with therapeutic implications for improving brain health and mitigating the development of cognitive impairment.