Characterizing Molecular and Synaptic Signatures in mouse models of Late-Onset Alzheimer's Disease Independent of Amyloid and Tau Pathology.

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. 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. 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. 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.