Effect of apoe genotype on enos regulation and the development of vcid - vascular contributions to cognitive impairment and dementia (vcid) occurs when the cerebrovasculature can no longer maintain…

The National Institute of Neurological Disorders and Stroke awarded The Roskamp Institute, Inc., $599,804 on September 1, 2026, under CFDA 93.853 (Extramural Research Programs in the Neurosciences and Neurological Disorders) to investigate the effect of apolipoprotein E (APOE) genotype on endothelial nitric oxide synthase (eNOS) regulation and the development of vascular contributions to cognitive impairment and dementia (VCID).

The research explores how APOE isoforms differentially influence eNOS homeostasis and nitric oxide bioavailability in brain endothelia to drive VCID progression. The project systematically determines the mechanisms by which APOE genotype and late-onset Alzheimer's disease conditions—including western diet and pathogenic amyloid/tau pathology—influence eNOS stabilization and the resulting impact of eNOS dysregulation on cerebrovascular dysfunction. The work addresses the role of the NOS3 and APOE4 genes as genetic factors influencing risk and progression of both late-onset Alzheimer's disease and cerebrovascular disease, with preliminary evidence suggesting APOE4 significantly impairs eNOS activity and accelerates microvascular dysfunction.

Performance occurs at The Roskamp Institute in Sarasota, Florida, with a period of performance extending through July 31, 2031. This is a project grant, the primary assistance type for extramural research supported by NINDS.

Effect of apoe genotype on enos regulation and the development of vcid - vascular contributions to cognitive impairment and dementia (vcid) occurs when the cerebrovasculature can no longer maintain homeostasis under metabolic, environmental, genetic and neurodegenerative insults, including late-onset alzheimer's disease (load). Cerebrovascular function relies on endothelial nitric oxide synthase (enos) activity, which maintains endothelial homeostasis, no bioavailability, and vascular integrity. Dysregulated enos activity drives endothelial dysfunction, and enos deficient mice develop several hallmarks of vcid pathology, including hypoperfusion, blood-brain barrier (BBB) breakdown, cerebral amyloid angiopathy, TAU pathology, white matter damage, and cognitive decline, suggesting a central role for enos in vcid and load progression. The NOS3 and APOE4 (apolipoprotein E4) genes are the only consistent genetic factor influencing the risk and progression of both load and cerebrovascular disease. Intriguingly, recent studies have demonstrated that load-associated vascular decline is mediated by enos dysregulation in an apoe genotype dependent manner, suggesting that apoe isoforms may differentially influence enos homeostasis to drive vcid, though the underlying mechanisms are poorly understood. Our preliminary studies show that apoe plays a constitutive role in maintaining enos homeostasis and no bioavailability in brain endothelia. However, APOE4 significantly impairs enos activity, and accelerates microvascular dysfunction, particularly in the presence of vcid stressors, leading to endothelial senescence, which may describe the increased prevalence and accelerated disease progression observed in APOE4 carriers. This project will take a systematic approach in determining the mechanisms by which apoe genotype and load conditions (e.g., western diet, pathogenic amyloid/TAU) influence enos stabilization (aim 1), and the resulting impact of enos dysregulation on cerebrovascular impairment (aim 2) and vcid progression (aim 3). To address these aims, this project will use a multi-modal approach in determining the effect of apoe genotype on enos homeostasis under load conditions including: apoe exposure and enos modulation in brain endothelia, in vitro BBB integrity and transit using a 3D brain-chip module, in vivo assessments of cerebrovascular abnormalities, cerebral blood flow, and BBB integrity, alongside evaluations of waste elimination and vcid pathology in load mice. At each of these stages, to strategically target enos, we will employ both pharmacologic and genetic approaches, using a well characterized enos enhancing peptide (cavnoxin), alongside established enos mouse models, which display constitutively enhanced or inhibited enos activity. In the short term, this project will not only advance our understanding of the role of apoe genotype and enos dysregulation on cerebrovascular decline but will also shed light on the molecular underpinnings driving the onset and progression of vcid and load. In the long term, IT is anticipated that the findings from this project will facilitate the development of novel therapeutic targets and strategies to treat neurodegenerative disorders.