Tryptophan is an essential amino acid and precursor to several compounds of neurobiological significance, including serotonin, melatonin, and nicotinamide adenine dinucleotide. However, the tryptophan-kynurenine metabolic pathway exhibits “double-edged sword” effects on neurons with neuroprotective metabolites and neurotoxic intermediates. Given its involvement in neurodegenerative diseases and recent reports of alterations in the pathway in response to obesity, we set out to investigate the potential moderating effect of the kynurenine/tryptophan ratio (KTR) on the relationship between adiposity and verbal memory performance in midlife. Our study is important in providing insight into mechanisms underlying the association between adiposity and cognition through the life course and sheds light on the role of metabolic risk factors before senescence. With the current epidemic of obesity and the expected age-related increase in dementia incidence, even a small association between obesity and cognitive decline may have far-reaching public health implications.

A total of 110 middle-aged adults aged 40-61 years participated in this cross-sectional study. Serum levels of kynurenine and tryptophan, body adiposity measured through bioimpedance, and non-contextual verbal memory performance on the California Verbal Learning Test, Second Edition (CVLT-II) were evaluated. Using factor analysis, the composite score of memory indices from Short Delay Free Recall, Long Delay Free Recall, and Long Delay Recognition tasks were calculated. We used linear regression models with the interaction between KTR and adiposity. Sex, age, years of education, and physical activity were included as covariates, as they predict cognitive performance.

Higher KTR was associated with greater adiposity (p < 0.01). Linear regression analyses for assessing interaction effects indicated that KTR moderated the relation between adiposity and composite memory score (F(7, 100) = 5.22, p < 0.001, R2 = 0.27). These results were robust across individual memory indices and composite memory scores. These findings remained significant even with adjusting for relevant covariates. Interestingly, the marginal effects of adiposity on composite memory score were estimated to be statistically significant and negative (higher adiposity = poorer memory) only when KTR was low (< 0.03).

The present study indicates that KTR may influence the association between adiposity and verbal memory in midlife as KTR moderated the relationship between adiposity and composite memory score even after adjusting for relevant covariates. In contrast to the notion that high KTR is related to increases in neurotoxic metabolites such as quinolinic acid, individuals with high adiposity and low KTR exhibited the weakest memory performance. Unfortunately, our study did not include measurements of quinolinic acid or kynurenic acid, which may have neuroprotective and anti-inflammatory properties. Future studies expanding the number of measured KT metabolites could shed light on the interactions between obesity and KTR on memory function in midlife.