## 1 Introduction  
Alzheimer's disease (AD) is characterized by the deposition of amyloid-\(\beta\) (A\(\beta\)) plaques and hyperphosphorylation of tau proteins, in parallel with significant impairments in neurovascular regulation [1], blood-brain barrier (BBB) integrity [2], and brain glucose metabolism [3]. Positron emission tomography with [18F]fluoro-2-deoxyglucose (18F-FDG-PET) has become a key tool in AD diagnosis, as it detects a decline in the cerebral metabolic rate of glucose--a phenomenon that can be observed even before the onset of clinical symptoms in individuals who will later develop dementia due to AD [4; 5]. Importantly, the decline in glucose metabolism occurs earlier and is more pronounced than the appearance of brain atrophy [6; 7]. One potential explanation for this early alteration in cerebral glucose uptake could be an abnormal delivery of glucose to the brain. Indeed, the loss of glucose transporters (GLUTs) from the BBB has been documented to occur before the onset of AD symptoms [8]. Moreover, postmortem studies on brains from patients with AD revealed that the decreased expression of GLUTs was significantly correlated with abnormal tau hyperphosphorylation, suggesting a link between impaired glucose transport across the BBB and the progression of AD pathology [9]. With its highly selective permeability, the BBB separates circulating blood from the brain's extracellular fluid. While not all patients with AD exhibit an overtly BBB disruption, it has been hypothesized that altered receptor-mediated transport could impair not only the clearance of toxic amyloid and tau proteins [10] but also the transport of glucose from plasma to the brain, contributing to the early metabolic changes observed in AD [11]. Studies examining brain glucose uptake predominantly leverage 18F-FDG-PET imaging. Indeed, 18F-FDG emits a radioactive signal upon entry into the central nervous system--which can be detected in both the parenchyma and cerebrospinal fluid (CSF). Once inside the brain cells, 18F-FDG is phosphorylated to FDG-6-phosphate which cannot be further metabolized [12]. Thus, this method enables the measurement of glucose uptake without fully reflecting subsequent glucose metabolism. Moreover, recent evidence supports the idea that the 18F-FDG signal in CSF spaces--particularly the ventricles--may convey meaningful information about altered glucose transport and metabolism in neurodegenerative diseases. Specifically, [PERSON] et al. [13] demonstrated that dynamic 18F-FDG PET can quantify ventricular CSF clearance, serving as a surrogate marker for glymphatic function, particularly relevant to amyloid and tau clearance in AD. The exact mechanisms governing neuronal glucose uptake remain poorly understood, raising critical questions about the interpretation of 18F-FDG-PET data. In the context of AD, is the cortical hypometabolism due to the loss of neuronal and glial cells, or is it linked to reduced 18F-FDG transport caused by BBB dysfunction? Moreover, the extent to which 18F-FDG uptake is influenced by alterations in glucose metabolism--potentially contributing to the pathogenesis of late-onset AD--has yet to be fully elucidated [14]. These questions should be examined in the context of Apolipoprotein E (APOE) genotype, the strongest genetic risk factor for late-onset AD. The presence of the APOE \(\epsilon\)4 allele not only increases the risk of developing AD but is also linked to a more aggressive disease progression, with more pronounced amyloid and tau pathology [15]. Recent studies have further demonstrated that APOE \(\epsilon\)4 affects brain cell metabolism, leading to reduced glycolytic activity and impaired mitochondrial respiration [16; 17]. To attempt to address some of these issues, the present study investigated the role of novel 18F-FDG-PET parameters in late-onset AD.