Association between large neutral amino acids and white matter hyperintensities in middle-aged adults at varying metabolic risk.

This investigation delves into the interplay between large neutral amino acids (LNAA) and metabolic syndrome (MetS) in midlife adults, examining their collective influence on brain structure. While LNAA, such as tryptophan and phenylalanine, are known to bolster cognition in youth, these relationships often reverse later in life. Our study hypothesized an earlier reversal of these benefits in middle-aged adults with MetS, potentially signaling premature brain aging. Eighty participants between 40-61 years underwent MetS component quantification, LNAA measurement via high-performance liquid chromatography, and brain imaging to evaluate white matter hyperintensities (WMH) volume and medial temporal lobe (MTL) cortical thickness. Our linear regression analyses, adjusting for sex, age, and education, revealed that phenylalanine levels moderated the relationship between MetS and WMH volume (F(6, 69) = 3.134, p < 0.05, R² = 0.214), suggesting the brain impact of MetS may be partly due to phenylalanine catabolism byproducts. LNAA metabolites did not significantly modulate the MetS-MTL cortical thickness relationship. These findings suggest that better understanding of the role of phenylalanine in the pathogenesis of cerebrovascular disease in midlife may be essential to developing early interventions to protect cognitive health. Further research is crucial to elucidate the longitudinal influence of LNAA and MetS on brain health, thereby informing strategies to mitigate cognitive decline.