Kotredes, Kevin P.Pandey, Ravi S.Persohn, ScottElderidge, KierraBurton, Charles P.Miner, Ethan W.Haynes, Kathryn A.Santos, Diogo Francisco S.Williams, Sean-PaulHeaton, NicholasIngraham, Cynthia M.Lloyd, ChristopherGarceau, DylanO’Rourke, RitaHerrick, SarahRangel-Barajas, ClaudiaMaharjan, SurendraWang, NianSasner, MichaelLamb, Bruce T.Territo, Paul R.Sukoff Rizzo, Stacey J.Carter, Gregory W.Howell, Gareth R.Oblak, Adrian L.2024-05-212024-05-212023-12-20Kotredes KP, Pandey RS, Persohn S, et al. Characterizing Molecular and Synaptic Signatures in mouse models of Late-Onset Alzheimer's Disease Independent of Amyloid and Tau Pathology. Preprint. bioRxiv. 2023;2023.12.19.571985. Published 2023 Dec 20. doi:10.1101/2023.12.19.571985https://hdl.handle.net/1805/40867Introduction: MODEL-AD is creating and distributing novel mouse models with humanized, clinically relevant genetic risk factors to more accurately mimic LOAD than commonly used transgenic models. Methods: We created the LOAD2 model by combining APOE4, Trem2*R47H, and humanized amyloid-beta. Mice aged up to 24 months were subjected to either a control diet or a high-fat/high-sugar diet (LOAD2+HFD) from two months of age. We assessed disease-relevant outcomes, including in vivo imaging, biomarkers, multi-omics, neuropathology, and behavior. Results: By 18 months, LOAD2+HFD mice exhibited cortical neuron loss, elevated insoluble brain Aβ42, increased plasma NfL, and altered gene/protein expression related to lipid metabolism and synaptic function. In vivo imaging showed age-dependent reductions in brain region volume and neurovascular uncoupling. LOAD2+HFD mice also displayed deficits in acquiring touchscreen-based cognitive tasks. Discussion: Collectively the comprehensive characterization of LOAD2+HFD mice reveal this model as important for preclinical studies that target features of LOAD independent of amyloid and tau.en-USAttribution 4.0 InternationalAlzheimer’s diseaseGeneticsHigh-fat dietLate-onset Alzheimer’s diseaseArticle