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protein regulates metabolic health and aging, with many benefits of a low protein diet resulting from reduced consumption of the three branched\u2010chain amino acids (BCAAs), leucine, isoleucine, and valine. Each BCAA has distinct physiological and molecular effects, and while restriction of protein or all three BCAAs improves cognition in mouse models of Alzheimer's disease (AD), the role of each individual BCAA on AD is unknown. Here, we investigate the impact of restricting leucine, isoleucine, or valine on metabolism, AD pathology, molecular signaling, and cognition in male and female 3xTg AD mice. Mice were fed BCAA\u2010restricted diets for nine months starting at six months of age. Restriction of either isoleucine or valine, but not leucine, improved metabolic health. We observed distinct, BCAA\u2010specific effects on AD pathology, molecular signaling, and gene expression in both sexes as well as shared molecular responses in males. Restricting any BCAA improved short\u2010term memory in males, with isoleucine having the strongest effect, while valine restriction led to the greatest cognitive benefits for females. These findings suggest that targeted BCAA restriction, particularly of isoleucine or valine, may form the basis of a novel sex\u2010specific approach to prevent or delay AD.<\/jats:p>","DOI":"10.1002\/advs.202515220","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T15:01:03Z","timestamp":1773327663000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Restriction of Individual Branched\u2010Chain Amino Acids has Distinct Effects on the Development and Progression of Alzheimer's Disease in 3xTg Mice"],"prefix":"10.1002","volume":"13","author":[{"given":"Reji","family":"Babygirija","sequence":"first","affiliation":[{"name":"Department of Medicine University of Wisconsin\u2010Madison  Madison Wisconsin USA"},{"name":"William S. 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