Abstract: A previous study has described a strong relationship between cardio- and cerebrovascular risk factors and the onset and progression of cognitive impairment (CI), and Alzheimer’s disease (AD), although their pathophysiology remains not completely understood (Balistreri, 2021). Consequently, our group has recently described the crucial role of the endothelium dysfunction, as well as of its dysfunctional endothelial glycocalyx (eGCX) and the related cellular and molecular mechanisms, in the onset of neurological pathologies, including stroke and AD (Balistreri et al., 2024; Balistreri and Monastero, 2025). The endothelium is not only the essential element of the cardiovascular system, but it also constitutes the essential component of any tissue in the human body, including the neurovascular unit and the brain–blood barrier (Balistreri and Monastero, 2023). In this case, their dysfunction triggers brain inflammation and the consequent pathological mechanisms linked to the onset and progression of CI and AD (Balistreri and Monastero, 2023). Therefore, the impact of eGCX dysfunction in the onset and progression of these diseases has also become of growing interest. The dysfunction of eGCX is characterized by its degradation, as shown by the high systemic levels of eGCX shedding products also described in AD (Balistreri et al., 2024; Balistreri and Monastero, 2025). However, data on this topic are still limited and mainly based on pre-clinical studies. Therefore, in this pilot study, we assessed whether the degradation of eGCX and endothelial dysfunction characterize AD, and in its prodromal phase, the so-called mild cognitive impairment (MCI). For this purpose, we quantified the systemic levels of certain eGCX degradation products and other molecules related to both eGCX and endothelium dysfunction, including Elabela-54, -21, and -32, syndecans (SDC) 1-4, thrombomodulin (CD141), and vascular endothelial growth factor (VEGF) in subjects with MCI and AD compared with healthy controls (HC).