Restriction of Individual Branched‐Chain Amino Acids has Distinct Effects on the Development and Progression of Alzheimer's Disease in 3xTg Mice

Reji Babygirija; Cara L. Green; Michelle M. Sonsalla; Izabelle Marie F. Le; Fan Xiao; Sarah Yandell; Mariah F. Calubag; Michaela E. Trautman; Anna Tobon; Ryan Matoska; Chung‐Yang Yeh; Charles I. Opara; Isaac Grunow; Diana Vertein; Sophia Schlorf; Bailey A. Knopf; Michael J. Rigby; David A. Harris; Mark P. Keller; Alan D. Attie; Luigi Puglielli; Cholsoon Jang; Dudley W. Lamming

doi:10.1002/advs.202515220

journal article·2026-05Open access

Restriction of Individual Branched‐Chain Amino Acids has Distinct Effects on the Development and Progression of Alzheimer's Disease in 3xTg Mice

Reji Babygirija, Cara L. Green, Michelle M. Sonsalla, Izabelle Marie F. Le, Fan Xiao, Sarah Yandell, Mariah F. Calubag, Michaela E. Trautman, Anna Tobon, Ryan Matoska, Chung‐Yang Yeh, Charles I. Opara, Isaac Grunow, Diana Vertein, Sophia Schlorf, Bailey A. Knopf, Michael J. Rigby, David A. Harris, Mark P. Keller, Alan D. Attie, Luigi Puglielli, Cholsoon Jang, Dudley W. Lamming

Advanced Science· Volume 13· Issue 30

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Source abstract

Abstract

ABSTRACT Dietary protein regulates metabolic health and aging, with many benefits of a low protein diet resulting from reduced consumption of the three branched‐chain 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‐restricted 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‐specific 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‐term 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‐specific approach to prevent or delay AD.

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Research context

OpenAlex topics: Alzheimer's disease research and treatments · Muscle metabolism and nutrition · Genetics, Aging, and Longevity in Model Organisms

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Medicine University of Wisconsin‐Madison Madison Wisconsin USA

William S. Middleton Memorial Veterans Hospital Madison Wisconsin USA

Cellular and Molecular Biology Graduate Program University of Wisconsin‐Madison Madison Wisconsin USA

Comparative Biomedical Sciences Graduate Program University of Wisconsin‐Madison Madison Wisconsin USA

Department of Biological Chemistry University of California Irvine California USA

Nutrition and Metabolism Graduate Program University of Wisconsin‐Madison Madison Wisconsin USA

Department of Biochemistry University of Wisconsin‐Madison Madison Wisconsin USA

Waisman Center University of Wisconsin‐Madison Madison Wisconsin USA

Neuroscience Training Program University of Wisconsin‐Madison Madison Wisconsin USA

Wisconsin Surgical Laboratory in Metabolism Department of Surgery University of Wisconsin‐Madison Madison Wisconsin USA

Wisconsin Nathan Shock Center of Excellence in the Basic Biology of Aging Madison Wisconsin USA

Comprehensive Diabetes Center University of Wisconsin Madison Wisconsin USA

Funding

National Institute of Neurological Disorders and Stroke · National Institute of General Medical Sciences · National Institute on Aging · National Institutes of Health · U.S. Department of Veterans Affairs · National Institute on Alcohol Abuse and Alcoholism · National Institute of Diabetes and Digestive and Kidney Diseases · Alzheimer's Association · Hevolution Foundation · Glenn Foundation for Medical Research

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