Abstract Background Altered resting‐state functional connectivity (RSFC) has been reported in early Alzheimer's disease (AD). Graph metrics derived from RSFC networks provide valuable insights into brain organization. However, their potential in characterizing early network dysfunction and their relationship with AD biomarkers and cognitive performance remains understudied. Methods Using RSFC data from 326 cognitively unimpaired (CU) individuals in the ALFA cohort (mean age=60.8, SD=4.74), we analyzed graph metrics in relation to cerebrospinal fluid (CSF) biomarkers. CSF Aβ42 and Aβ40 were assessed with the NeuroToolKit, a panel of exploratory robust prototype assays, while p ‐tau181 was measured with the Elecsys® Phospho‐Tau (181P) CSF immunoassay (both Roche Diagnostics International Ltd). Interactions with age and sex were further inspected. RSFC networks were computed from 218 regions (Brainnetome atlas) using CONN, and thresholded at a density of 35%. The following graph metrics were extracted: average path length (APL), Local Efficiency (LE), Betweenness Centrality (BC), Closeness Centrality (CC), and Strength. Linear regression models assessed associations between CSF biomarkers and graph metrics, adjusting for age, sex, years of education, and APOE ‐ε4. Interactions between CSF biomarkers and graph metrics were analyzed for their impact on longitudinal cognitive measures (Preclinical Alzheimer Cognitive Composite [PACC]; mean follow‐up=3.35 y, SD=0.53). Results We found a positive main effect of CSF Aβ42/40 ( p = 0.011) and p ‐tau181 ( p = 0.012) on BC of the Dorsal Attention Network (DAN) (Figure 1). Significant interactions between Aβ42/40 and sex were observed on the APL, CC and Strength of the Default Mode Network (DMN) (Figure 2). Finally, significant interactions were observed between Aβ42/40 and graph metrics of the DMN— APL ( p = 0.005), LE ( p = 0.009), and CC ( p = 0.008)— on PACC changes (Figure 3). Conclusion Our data suggest that, in CU individuals, soluble Ab and p ‐tau exert opposite effects in the DAN information flow. Moreover, our interaction models suggest that a lower integration between DMN and the rest of the brain, as well as a lower centrality of DMN regions might be beneficial to preserve cognitive performance in the presence of AD. This study highlights the role of network topology in early AD and its potential to support cognitive resilience, providing potential targets for intervention.

Abstract Background Lipid accumulation in the liver leads to metabolic‐associated fatty liver disease (MAFLD), a pathology that has been associated with Alzheimer's disease (AD). MAFLD relates to alterations in lipid metabolism in several organs, including the brain. Impaired lipid metabolism in the brain leads to synthesizing toxic compounds, such as ceramides. Ceramide accumulation in the brain may lead to neuroinflammation. However, it is unknown if APP/PS1 mice develop alterations in lipid metabolism in the liver and whether this alteration may be associated with ceramide accumulation and neuroinflammation in the brain. Method We determined the presence of neutral lipids and ceramides in the liver of six‐month‐old male APP/PS1 transgenic (TG) and their wild‐type (WT) littermate mice by histological staining and ELISA, respectively. We also determined the expression and localization of ceramides and glial fibrillary acidic protein (GFAP)+ astrocytes in the brain by immunofluorescence. Result We observed higher ceramide content and microvesicular lipid accumulation in TG mice's hepatocytes compared to WT mice, an event accompanied by altered hepatic cytology. TG mice also showed an accumulation of ceramides in the somatosensory and entorhinal cortices compared to WT mice. Moreover, a higher number of GFAP+astrocyte with ceramide content was found in the stratum radiatum and entorhinal cortex of TG than WT mice. Conclusion TG mice develop an altered lipid metabolism in the liver that may be associated with an enhanced accumulation of ceramides. Ceramides were highly expressed in GFAP+ astrocytes in TG mice, but not in WT controls. Our results add information about lipid metabolic alterations that may be associated with the onset of AD pathology, with special emphasis in the liver – brain axis.

Abstract Background Mitochondrial dysfunction has been indicated in the development of AD/ADRD. Complex I defects from the ETC of mitochondrial respiration have been associated with ROS production and neurodegeneration. Herein, novel mitochondrial complex I inhibitors were synthesized and biologically characterized to develop complex I PET radiotracers Method Radiochemistry was conducted to radiolabel the identified complex I inhibitor with F‐18 and the radiotracer was characterized in mice with PET/CT imaging for its biodistribution and brain penetration. Result The radiotracer can quickly enter the brain and shows a promising clearance profile. Blocking studies with the parent compound demonstrated good specificity. Conclusion A new complex I PET radiotracer was successfully synthesized and characterized in mice by PET/CT studies.