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Here, using unbiased lipidomic approaches and direct biochemical assessments, we profiled Land's cycle lipid remodeling in the hippocampus, frontal cortex, and temporal\u2010parietal\u2010entorhinal cortices of human amyloid beta precursor protein (\u0391\u03b2PP<\/jats:styled-content>) over\u2010expressing mice. We identified a cortex\u2010specific hypo\u2010metabolic signature at symptomatic onset and a cortex\u2010specific hyper\u2010metabolic signature of Land's cycle glycerophosphocholine remodeling over the course of progressive behavioral decline. When N5 TgCRND<\/jats:styled-content>8 and \u0391\u03b2PPS<\/jats:sup><\/jats:styled-content>we<\/jats:sup>\/PSI<\/jats:styled-content>dE9<\/jats:sup> mice first exhibited deficits in the Morris Water Maze, levels of lyso\u2010<\/jats:italic>phosphatidylcholines, LPC<\/jats:styled-content>(18:0\/0:0), LPC<\/jats:styled-content>(16:0\/0:0), LPC<\/jats:styled-content>(24:6\/0:0), LPC<\/jats:styled-content>(25:6\/0:0), the lyso<\/jats:italic>\u2010platelet\u2010activating factor (PAF<\/jats:styled-content>), LPC<\/jats:styled-content>(O\u201018:0\/0:0), and the PAF<\/jats:styled-content>, PC<\/jats:styled-content>(O\u201022:6\/2:0), declined as a result of reduced calcium\u2010dependent cytosolic phospholipase A2<\/jats:sub>\u03b1 (cPLA<\/jats:styled-content>2<\/jats:sub>\u03b1) activity in all cortices but not hippocampus. Chronic intermittent hypoxia, an environmental risk factor that triggers earlier learning memory impairment in \u0391\u03b2PPS<\/jats:sup><\/jats:styled-content>we<\/jats:sup>\/PSI<\/jats:styled-content>dE9<\/jats:sup> mice, elicited these same metabolic changes in younger animals. Thus, this lipidomic signature of phenoconversion appears age\u2010independent. By contrast, in symptomatic N5 TgCRND<\/jats:styled-content>8 mice, cPLA<\/jats:styled-content>2<\/jats:sub>\u03b1 activity progressively increased; overall Lyso\u2010<\/jats:italic>phosphatidylcholines (LPC<\/jats:styled-content>) and LPC<\/jats:styled-content>(O) and PC<\/jats:styled-content>(O\u201018:1\/2:0) levels progressively rose. Enhanced cPLA<\/jats:styled-content>2<\/jats:sub>\u03b1 activity was only detected in transgenic mice; however, age\u2010dependent increases in the PAF acetylhydrolase 1b \u03b11<\/jats:sub> to \u03b12<\/jats:sub> expression ratio, evident in both transgenic and non\u2010transgenic mice, reduced PAF<\/jats:styled-content> hydrolysis thereby contributing to PAF<\/jats:styled-content> accumulation. Taken together, these data identify distinct age\u2010independent and age\u2010dependent disruptions in Land's cycle metabolism linked to symptomatic onset and progressive behavioral decline in animals with pre\u2010existing \u0391\u03b2 pathology.<\/jats:p><\/jats:sec>Open science badges<\/jats:title><\/jats:p>This article has received a badge for *Open Materials*<\/jats:bold> because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https:\/\/cos.io\/our-services\/open-science-badges\/<\/jats:ext-link>.<\/jats:p><\/jats:sec>\nimage<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14560","type":"journal-article","created":{"date-parts":[[2018,7,25]],"date-time":"2018-07-25T02:00:32Z","timestamp":1532484032000},"page":"499-517","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Distinct disruptions in Land's cycle remodeling of glycerophosphocholines in murine cortex mark symptomatic onset and progression in two Alzheimer's disease mouse models"],"prefix":"10.1111","volume":"149","author":[{"given":"Matthew W.","family":"Granger","sequence":"first","affiliation":[{"name":"Neural Regeneration Laboratory Ottawa Institute of Systems Biology Centre for Catalysis Research and Innovation University of Ottawa Brain and Mind Research Institute Ottawa ON Canada"},{"name":"Department of Biochemistry, Microbiology, and Immunology University of Ottawa Ottawa ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurology Minhang Branch Zhongshan Hospital Fudan University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin F.","family":"Fowler","sequence":"additional","affiliation":[{"name":"Neural Regeneration Laboratory Ottawa Institute of Systems Biology Centre for Catalysis Research and Innovation University of Ottawa Brain and Mind Research Institute Ottawa ON Canada"},{"name":"Department of Biochemistry, Microbiology, and Immunology University of Ottawa Ottawa ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre P.","family":"Blanchard","sequence":"additional","affiliation":[{"name":"Neural Regeneration Laboratory Ottawa Institute of Systems Biology Centre for Catalysis Research and Innovation University of Ottawa Brain and Mind Research Institute Ottawa ON Canada"},{"name":"Department of Biochemistry, Microbiology, and Immunology University of Ottawa Ottawa ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew W.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Neural Regeneration Laboratory Ottawa Institute of Systems Biology Centre for Catalysis Research and Innovation University of Ottawa Brain and Mind Research Institute Ottawa ON Canada"},{"name":"Department of Biochemistry, Microbiology, and Immunology University of Ottawa Ottawa ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha P. 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