Constitutive NOS Production Is Modulated by Alzheimer's Disease Pathology Depending on APOE Genotype

Both the endothelial (eNOS) and the neuronal (nNOS) isoforms of constitutive Nitric Oxide Synthase have been implicated in vascular dysfunctions in Alzheimer's disease (AD). We aimed to explore the relationship between amyloid pathology and NO dynamics by comparing the cerebrospinal fluid (CSF) levels of nNOS and eNOS of 8 healthy controls (HC) and 27 patients with a clinical diagnosis of Alzheimer's disease and isolated CSF amyloid changes, stratified according to APOE epsilon genotype (APOE epsilon 3 = 13, APOE epsilon 4 = 14). Moreover, we explored the associations between NOS isoforms, CSF AD biomarkers, age, sex, cognitive decline, and blood-brain barrier permeability. In our cohort, both eNOS and nNOS levels were increased in APOE epsilon 3 with respect to HC and APOE epsilon 4. CSF eNOS inversely correlated with CSF Amyloid-beta 42 selectively in carriers of APOE epsilon 3; CSF nNOS was negatively associated with age and CSF p-tau only in the APOE epsilon 4 subgroup. Increased eNOS could represent compensative vasodilation to face progressive A beta-induced vasoconstriction in APOE epsilon 3, while nNOS could represent the activation of NO-mediated plasticity strategies in the same group. Our results confirm previous findings that the APOE genotype is linked with different vascular responses to AD pathology.