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Early detection and understanding of risk factors and their downstream effects are therefore crucial. Animal models provide valuable tools to study these prodromal stages. We investigated various levels of genetic risk for AD using mice expressing the three major human APOE alleles in place of mouse APOE. We leverage these mouse models utilizing high-resolution magnetic resonance diffusion imaging, due to its ability to provide multiple parameters that can be analysed jointly. We examine how APOE genotype interacts with age, sex, diet, and immunity to yield jointly discernable changes in regional brain volume and fractional anisotropy, a sensitive metric for brain water diffusion. Our results demonstrate that genotype strongly influences the caudate putamen, pons, cingulate cortex, and cerebellum, while sex affects the amygdala and piriform cortex bilaterally. Immune status impacts numerous regions, including the parietal association cortices, thalamus, auditory cortex, V1, and bilateral dentate cerebellar nuclei. Risk factor interactions particularly affect the amygdala, thalamus, and pons. APOE2 mice on a regular diet exhibited the fewest temporal changes, suggesting resilience, while APOE3 mice showed minimal effects from a high-fat diet (HFD). HFD amplified aging effects across multiple brain regions. The interaction of AD risk factors, including diet, revealed significant changes in the periaqueductal gray, pons, amygdala, inferior colliculus, M1, and ventral orbital cortex. Future studies should investigate the mechanisms underlying these coordinated changes in volume and texture, potentially by examining network similarities in gene expression and metabolism, and their relationship to structural pathways involved in neurodegenerative disease progression.<\/jats:p>","DOI":"10.1101\/2025.02.05.636582","type":"posted-content","created":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T23:40:40Z","timestamp":1738885240000},"source":"Crossref","is-referenced-by-count":1,"title":["Network Biomarkers of Alzheimer\u2019s Disease Risk Derived from Joint Volume and Texture Covariance Patterns in Mouse Models"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6115-719X","authenticated-orcid":false,"given":"Eric W.","family":"Bridgeford","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA"},{"name":"Stanford University, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaewon","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Radiology Department, Duke University Medical School, Durham, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Mahzarnia","sequence":"additional","affiliation":[{"name":"Radiology Department, Duke University Medical School, Durham, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacques A.","family":"Stout","sequence":"additional","affiliation":[{"name":"Brain Imaging and Analysis Center, Duke University Medical School, Duke University Medical School, Durham, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hae Sol","family":"Moon","sequence":"additional","affiliation":[{"name":"Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zay Yar","family":"Han","sequence":"additional","affiliation":[{"name":"Radiology Department, Duke University Medical School, Durham, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua T.","family":"Vogelstein","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Badea","sequence":"additional","affiliation":[{"name":"Radiology Department, Duke University Medical School, Durham, NC, USA"},{"name":"Brain Imaging and Analysis Center, Duke University Medical School, Duke University Medical School, Durham, NC, USA"},{"name":"Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, USA"},{"name":"Neurology Department, Duke University Medical School, Duke University Medical School, Durham, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041023573738000_2025.02.05.636582v1.1","doi-asserted-by":"crossref","unstructured":"EH Corder , AM Saunders , WJ Strittmatter , D. 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