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Emerging evidence suggests ketone metabolism may help the brain adapt to energy stress in neurodegenerative diseases such as Alzheimer\u2019s disease, although its role in constitutive brain function in normal aging is poorly understood. Using iPSC-derived human neurons and adult-inducible, neuron-specific\n                  <jats:italic>Bdh1<\/jats:italic>\n                  knockout mice, we show that ketone body metabolism is essential for maximum energy production, neuronal function, and mouse survival\u2014even under normal nutritional conditions. Mechanistically, phenotypes of\n                  <jats:italic>Bdh1<\/jats:italic>\n                  knockout neurons are mitigated by provision of acetoacetate, a downstream energy metabolite. Moreover, loss of neuronal ketone oxidation markedly increases mortality and memory deficits in Alzheimer\u2019s disease model mice. These findings identify ketones as critical neuronal fuels, with particular importance during neurodegeneration. While non-energetic activities of ketone bodies are increasingly appreciated, oxidation for energy provision is an essential mechanism for normal function in neurons and mice. Targeting the energetic function of ketones may thus offer new therapeutic strategies for both aging and neurodegenerative diseases such as Alzheimer\u2019s.\n                <\/jats:p>","DOI":"10.64898\/2026.03.24.712448","type":"posted-content","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T19:30:26Z","timestamp":1774639826000},"source":"Crossref","is-referenced-by-count":1,"title":["Requirement for oxidation of neuronal ketone bodies in aging and neurodegeneration"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7341-7403","authenticated-orcid":false,"given":"Joyce","family":"Yang","sequence":"first","affiliation":[{"name":"Gladstone Institute of Neurological Diseases, Gladstone Institutes, San Francisco CA USA"},{"name":"Neuroscience Graduate Program, University of California San Francisco, San Francisco CA 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