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Mice were subjected to a control diet or a high\u2010fat\/high\u2010sugar diet (LOAD2+HFD). We assessed disease\u2010relevant outcome measures in plasma and brain including neuroinflammation, A\u03b2, neurodegeneration, neuroimaging, and multi\u2010omics.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>By 18 months, LOAD2+HFD mice exhibited sex\u2010specific neuron loss, elevated insoluble brain A\u03b242, increased plasma neurofilament light chain (NfL), and altered gene\/protein expression related to lipid metabolism and synaptic function. Imaging showed reductions in brain volume and neurovascular uncoupling. Deficits in acquiring touchscreen\u2010based cognitive tasks were observed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>The comprehensive characterization of LOAD2+HFD mice reveals that this model is important for preclinical studies seeking to understand disease trajectory and progression of LOAD prior to or independent of amyloid plaques and tau tangles.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>By 18 months, unlike control mice (e.g., LOAD2 mice fed a control diet, CD), LOAD2+HFD mice presented subtle but significant loss of neurons in the cortex, elevated levels of insoluble Ab42 in the brain, and increased plasma neurofilament light chain (NfL).<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Transcriptomics and proteomics showed changes in gene\/proteins relating to a variety of disease\u2010relevant processes including lipid metabolism and synaptic function.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>In vivo imaging revealed an age\u2010dependent reduction in brain region volume (MRI) and neurovascular uncoupling (PET\/CT).<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>LOAD2+HFD mice also demonstrated deficits in acquisition of touchscreen\u2010based cognitive tasks.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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