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Astrocytes play a central role in brain homeostasis and are implicated in multiple neurodegenerative diseases. Although numerous studies have investigated global changes in brain metabolism, redox status, gene expression and epigenetic markers in AD, the intricate interplay between different metabolic processes, particularly in astrocytes, remains poorly understood. Numerous studies have implicated amyloid\u2010\u03b2 and the amyloid\u2010\u03b2 precursor in the development and progression of AD. To determine the effects of amyloid\u2010\u03b2 peptides or the impact of amyloid\u2010\u03b2 precursor protein processing on astrocyte metabolism, we differentiated astrocytes from induced pluripotent stem cells derived from people with early onset familial AD and controls. This study demonstrates that familial AD\u2010derived astrocytes exhibit significantly more changes in their metabolism including glucose uptake, glutamate uptake and lactate release, with increases in oxidative and glycolytic metabolism compared to acute amyloid\u2010\u03b2 exposure. In addition to changes in major metabolic pathways including glutamate, purine and arginine metabolism and the citric acid cycle, we demonstrate evidence of gliosis in familial AD astrocytes highlighting a potential pathological hallmark. This suggests that chronic alterations in metabolism may occur very early in the disease process and present significant risk factors for disease progression for patients with early onset AD. These findings may also reveal important drivers of disease in late onset dementia and highlights key targets for potential diagnostic features and therapeutic agents in the future.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc16267-fig-0008-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.16267","type":"journal-article","created":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T00:39:18Z","timestamp":1734568758000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Altered metabolic function induced by A\u03b2\u2010oligomers and\n                    <scp>PSEN1<\/scp>\n                    mutations in\n                    <scp>iPSC<\/scp>\n                    \u2010derived astrocytes"],"prefix":"10.1111","volume":"169","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8504-9801","authenticated-orcid":false,"given":"Richard J.","family":"Elsworthy","sequence":"first","affiliation":[{"name":"School of Sport, Exercise and Rehabilitation Sciences, College of Life and Environmental Sciences University of Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattea J.","family":"Finelli","sequence":"additional","affiliation":[{"name":"Biodiscovery Institute, University of Nottingham, School of Medicine University Park Nottingham NG7 2RD  Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Aqattan","sequence":"additional","affiliation":[{"name":"School of Biology, College of Health and Life Sciences Aston University  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connor","family":"Dunleavy","sequence":"additional","affiliation":[{"name":"School of Sport, Exercise and Rehabilitation Sciences, College of Life and Environmental Sciences University of Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne","family":"King","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience University of Sheffield  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adele","family":"Ludlam","sequence":"additional","affiliation":[{"name":"School of Pharmacy, College of Health and Life Sciences Aston University  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta A.","family":"Tarczyluk","sequence":"additional","affiliation":[{"name":"School of Biology, College of Health and Life Sciences Aston University  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie L.","family":"Allen","sequence":"additional","affiliation":[{"name":"School of Sport, Exercise and Rehabilitation Sciences, College of Life and Environmental Sciences University of Birmingham  Birmingham UK"},{"name":"NIHR Birmingham Biomedical Research Centre University Hospitals Birmingham NHS Foundation Trust, University of Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Prosser","sequence":"additional","affiliation":[{"name":"School of Sport, Exercise and Rehabilitation Sciences, College of Life and Environmental Sciences University of Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Chen","sequence":"additional","affiliation":[{"name":"Centre for Analytical Bioscience, Advanced Materials &amp; Healthcare Technologies Division, School of Pharmacy University of Nottingham  Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra Martinez","family":"Jarquin","sequence":"additional","affiliation":[{"name":"Centre for Analytical Bioscience, Advanced Materials &amp; Healthcare Technologies Division, School of Pharmacy University of Nottingham  Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong H.","family":"Kim","sequence":"additional","affiliation":[{"name":"Centre for Analytical Bioscience, Advanced Materials &amp; Healthcare Technologies Division, School of Pharmacy University of Nottingham  Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Brown","sequence":"additional","affiliation":[{"name":"School of Pharmacy, College of Health and Life Sciences Aston University  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. 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