Distinct effects of restricting individual branched-chain amino acids on the development and progression of Alzheimer’s disease in 3xTg mice

Dietary protein is a critical regulator of metabolic health and aging in diverse species, and many of the benefits of low-protein diets are recapitulated by restriction of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. In mouse models of Alzheimer’s disease (AD), dietary supplementation with BCAAs worsens AD neuropathology, while restriction of any of the BCAAs improves cognitive deficits. We recently discovered that each BCAA has distinct metabolic effects, with the restriction of isoleucine alone being sufficient to improve metabolic health and extend lifespan and healthspan in genetically diverse mice. Here, we investigate the effect of restricting each individual BCAA on metabolic health and the development and progression of AD in the 3xTg mouse model. We find that restriction of isoleucine and valine, but not leucine, promotes metabolic health. Restricting any of the three BCAAs improved short-term memory in males, with isoleucine restriction having the strongest effect, while restricting valine has the greatest cognitive benefits in females. Restriction of each BCAA had distinct effects on AD pathology, mTOR signaling, autophagy, and survival. Transcriptomic analysis of the brain revealed both distinct and shared, and highly sex-specific, molecular impacts of restricting each BCAA, and we identify a set of significantly altered pathways strongly associated with reduced AD pathology and improved cognitive performance in males. Our findings suggest that restricting any of the BCAAs, particularly isoleucine or valine, may form the basis of a novel sex-specific approach to prevent or delay the progression of AD.