18F-Fluorodeoxyglucose Uptake in Cerebrospinal Fluid Reflects Both Brain Glucose Demand and Impaired Blood–Brain Barrier Transport in Alzheimer’s Disease

Glucose delivery to the brain requires transporters at the blood–brain barrier (BBB), whose downregulation may be associated with neuronal deficits in Alzheimer’s disease (AD). Whether this downregulation is due to reduced demand or primary BBB dysfunction remains unclear. We investigated novel 18F-Fluorodeoxyglucose Positron Emission Tomography (18F-FDG-PET) measures, namely ventricles (FDGVentricles) and cortical uptake (FDGCortex), and the FDGVentricles/FDGCortex ratio in 224 patients with AD compared to those in 35 controls (CTRLs). AD patients showed lower FDGCortex and FDGVentricles and higher cerebrospinal fluid (CSF) lactates than CTRLs. We found a positive correlation between FDGCortex and FDGVentricles in both groups, although this was less strong in AD patients (AD: r = 0.358; p < 0.001; CTRL: r = 0.516; p = 0.003). Multivariate regression analyses showed that only older age was associated with reduced FDGCortex and FDGVentricles in CTRLs. Conversely, lower FDGCortex was associated with higher Qalb and higher plasma glucose levels within the AD group. Moreover, lower FDGVentricles and FDGVentricles/FDGCortex ratios were associated with elevated CSF lactates in this group. Stratifying AD patients by Apolipoprotein E (APOE) genotype revealed distinct patterns. In APOE ε3 homozygotes, FDGCortex showed no associations, while FDGVentricles and FDGVentricles/FDGCortex were negatively associated with CSF lactate. In APOE ε4 carriers, lower FDGCortex was linked to higher plasma glucose and QAlb, whereas FDGVentricles and FDGVentricles/FDGCortex were positively associated with CSF p-tau/Aβ42. Our findings suggest that, in patients with AD, FDGVentricles and the FDGVentricles/FDGCortex ratio may reflect alterations in brain metabolism and glucose extraction capacity. These parameters are differently linked with age, BBB integrity, and metabolic dysfunction (CSF lactates), according to APOE genotype.