## 4 Discussion  
Our study highlights the potential utility of two newly introduced 18F-FDG-PET parameters--\(\mathrm{FDG_{Ventircles}}\) and the \(\mathrm{FDG_{Ventircles}}/\mathrm{FDG_{Cortex}}\) ratio--in exploring metabolic dysfunctions in late-onset AD. In our cohort, as expected, no difference was found in BBB permeability, evaluated as Qalb, between the AD and CTRL groups. While the literature does not support the notion of a fully disrupted BBB in AD, it has been shown that early BBB disfunction occurs and exacerbates protein misfolding and neurodegeneration [5]. On the other hand, our AD patients showed higher levels of CSF lactates, supporting the hypothesis that changes in energy metabolism--a hallmark of normal aging processes--may also be involved in late-onset AD [26]. Indeed, when neurons experience an increased demand for oxidative \begin{table}
\begin{tabular}{c c c c c} \hline \hline  & \multicolumn{2}{c}{**APOE \(\epsilon 3\)**} & \multicolumn{2}{c}{**APOE \(\epsilon 4\)**} \\ \hline  & \(\beta\) & \(p\) & \(\beta\) & \(p\) \\ \hline \(\mathrm{FDG_{Cortex}}\) & & & & \\ Age & \(-0.126\) & \(0.900\) & \(-0.032\) & \(0.747\) \\ Plasma glucose (mg/dL) & \(-0.059\) & \(0.544\) & \(-0.268\) & \(\mathbf{0.010}\) \\ Qalb & \(-0.138\) & \(0.166\) & \(-0.240\) & \(\mathbf{0.019}\) \\ CSF p-tau/A\(\beta_{42}\) & \(-0.096\) & \(0.311\) & \(-0.071\) & \(0.468\) \\ CSF lactates & \(0.141\) & \(0.151\) & \(-0.085\) & \(0.431\) \\ Adjusted R\({}^{2}\) & \multicolumn{2}{c}{\(-0.001\)} & \multicolumn{2}{c}{\(0.126\)} \\ \hline \(\mathrm{FDG_{Ventircles}}\) & & & & \\ Age & \(-0.247\) & \(\mathbf{0.008}\) & \(-0.289\) & \(\mathbf{0.002}\) \\ Plasma glucose (mg/dL) & \(0.061\) & \(0.511\) & \(-0.080\) & \(0.395\) \\ Qalb & \(-0.032\) & \(0.742\) & \(-0.218\) & \(\mathbf{0.020}\) \\ CSF p-tau/A\(\beta_{42}\) & \(-0.057\) & \(0.531\) & \(0.253\) & \(\mathbf{0.006}\) \\ CSF lactates & \(-0.201\) & \(\mathbf{0.035}\) & \(-0.142\) & \(0.155\) \\ Adjusted R\({}^{2}\) & \multicolumn{2}{c}{\(0.069\)} & \multicolumn{2}{c}{\(0.261\)} \\ \hline \(\mathrm{FDG_{Ventircles}}/\mathrm{FDG_{Cortex}}\) & & & & \\ Age & \(-0.238\) & \(\mathbf{0.010}\) & \(-0.303\) & \(\mathbf{0.002}\) \\ Plasma glucose (mg/dL) & \(0.089\) & \(0.341\) & \(0.071\) & \(0.457\) \\ Qalb & \(0.041\) & \(0.669\) & \(-0.120\) & \(0.202\) \\ CSF p-tau/A\(\beta_{42}\) & \(0.015\) & \(0.866\) & \(0.334\) & \(\mathbf{<0.001}\) \\ CSF lactates & \(-0.260\) & \(\mathbf{0.006}\) & \(-0.118\) & \(0.243\) \\ Adjusted R\({}^{2}\) & \multicolumn{2}{c}{\(0.086\)} & \multicolumn{2}{c}{\(0.248\)} \\ \hline \hline \end{tabular}
\end{table} 
Table 3: Multivariate regression analyses in APOE \(\epsilon 3\) and APO \(\epsilon 4\) patients. substrates, particularly lactate, astrocytes may supply this demand through their high glycolytic capacity leveraging the Astrocyte-Neuron Lactate Shuttle [27]. Considering the 18F-FDG-PET parameters, both cortical and cerebrospinal fluid 18F-FDG uptake (FDG\({}_{\text{Cortex}}\) and FDG\({}_{\text{Ventircles}}\)) were significantly lower in patients with AD compared to CTRLs. Reduced 18F-FDG uptake in cortical gray matter is widely recognized as a key feature of AD and a valuable marker for predicting cognitive decline [3]. The underlying concept is that neurodegeneration leads to the loss of neurons and glial cells responsible for glucose uptake or to a reduction in their metabolic efficiency. However, FDG\({}_{\text{Ventircles}}\) does not represent cellular uptake itself. Its reduction in patients with AD may potentially correspond to a reduced glucose demand from the brain. Indeed, we found a significant correlation between the FDG\({}_{\text{Ventircles}}\) and the FDG\({}_{\text{Cortex}}\) levels in both CTRLs and patients, supporting the hypothesis of a physiological \"brain pull effect\" in which the brain's glucose demand influences its CSF levels [28].