Role of APOE in Diabetes-Related Risk for AD

The APOE ε4 allele is the most prominent genetic predisposition for sporadic Alzheimer’s disease (AD). Amylin, a neuroendocrine hormone co-secreted with insulin from the pancreas, has biochemical characteristics of amyloid and is hypersecreted in persons with prediabetes. We and others reported that amylin forms neurotoxic hetero-oligomers with β-amyloid (Aβ) and accumulates in cerebral plaques and blood vessel walls, in the brains of persons with AD. Our preliminary data show that the average brain amylin level in APOE4 carriers with type-2 diabetes and AD is >4-fold higher compared to non- diabetic APOE4 carriers with AD. The brain microvasculature presents amylin and amylin-Aβ pathologies, whereas brains of cognitively normal diabetics with other APOE variants lack amylin deposits. Of note, apoE4 was identified by immunohistochemistry (IHC) on amylin amyloid-containing pancreatic tissue from humans and is believed to modulate amylin oligomerization. Using laboratory models of diabetes, we found that intravenously infused apoE4 protein in rats expressing human amylin specifically in the pancreas led to increased brain amylin accumulation. Further, we showed that increased human amylin levels in the blood in rats disrupts Aβ efflux through modulating LRP1-Pgp levels. These results suggest the hypothesis that diabetes promotes brain amylin accumulation and amylin-Aβ pathology via isoform-dependent amylin-apoE interactions. In this project, we will combine human-based and model-based analyses to delineate biological mechanisms underlying the association between amylin-apoE interaction and AD pathology. To identify conditions (metabolic status and APOE genotype) associated with increased risk for brain amylin pathology, we will use existing (published) amylin-related data paired with clinical data. To test the hypothesis that the presence of apoE4 in plasma accelerates amylin oligomerization leading to brain blood vessel injury and increased diffusion of oligomerized amylin in the brain, we generated APOE-/-Amy-/- mice by crossing amylin knockout mice (Amy-/-) with APOE knockout mice which will be intravenously infused with specific combinations of human amylin and apoE4/E3/E2. We will further use mice humanized for amylin and ApoE to test ApoE isoform-specific alterations in cerebrovascular amylin deposition and β- amyloid homeostasis in the absence of AD-like Aβ pathology. The completion of our proposed studies will help understand: 1, the relationships between APOE4/E3/E2 isoforms and brain amylin, amylin- Aβ pathologies; 2, effects of isoform-dependent amylin-APOE interactions on the blood-brain barrier and cerebral Aβ efflux; and 3, the interaction of plasma amylin-APOE complexes with Aβ pathology. Outcomes of our proposed studies will determine whether amylin-APOE allele distributions, circulating amylin-apoE molecular complexes and/or the formation of amylin-Aβ-apoE aggregates can become novel AD biomarkers.