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. 2024 Jul 27;16(1):167.
doi: 10.1186/s13195-024-01531-7.

Sex-specific associations of kynurenic acid with neopterin in Alzheimer's disease

Anne-Brita Knapskog  1 , Trine Holt Edwin  1 , Per Magne Ueland  2 , Arve Ulvik  2 , Evandro Fei Fang  3   4 , Rannveig Sakshaug Eldholm  5   6 , Nathalie Bodd Halaas  7   8 , Lasse M Giil  9   10 , Ingvild Saltvedt  5   6 , Leiv Otto Watne  7   11   12 , Mari Aksnes  13
Affiliations

Sex-specific associations of kynurenic acid with neopterin in Alzheimer's disease

Anne-Brita Knapskog et al. Alzheimers Res Ther. .

Abstract

Background: Sex differences in neuroinflammation could contribute to women's increased risk of Alzheimer's disease (AD), providing rationale for exploring sex-specific AD biomarkers. In AD, dysregulation of the kynurenine pathway (KP) contributes to neuroinflammation and there is some evidence of sex differences in KP metabolism. However, the sex-specific associations between KP metabolism and biomarkers of AD and neuroinflammation need to be explored further.

Methods: Here we investigate sex differences in cerebrospinal fluid concentrations of seven KP metabolites and sex-specific associations with established AD biomarkers and neopterin, an indicator of neuroinflammation. This study included 311 patients with symptomatic AD and 105 age-matched cognitively unimpaired (CU) controls, followed for up to 5 years.

Results: We found sex differences in KP metabolites in the AD group, with higher levels of most metabolites in men, while there were no sex differences in the CU group. In line with this, more KP metabolites were significantly altered in AD men compared to CU men, and there was a trend in the same direction in AD women. Furthermore, we found sex-specific associations between kynurenic acid and the kynurenic acid/quinolinic acid ratio with neopterin, but no sex differences in the associations between KP metabolites and clinical progression.

Discussion: In our cohort, sex differences in KP metabolites were restricted to AD patients. Our results suggest that dysregulation of the KP due to increased inflammation could contribute to higher AD risk in women.

Keywords: Alzheimer disease; Biomarkers; Cerebrospinal fluid; Kynurenic acid; Kynurenine pathway; Longitudinal case control study; Mitophagy; Quinolinic acid; Sex differences; Tryptophan.

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Conflict of interest statement

A.B.K. has been principal investigator on the Roche drug trial BN29553, on the Boehringer-Ingelheim drug trial 1346.0023, and the Novo Nordisk drug trial NN6535-4730. T.H.E. has been investigator on the clinical trial Roche BN29553; and T.H.E. and I.S. have worked on the Boehringer-Ingelheim clinical trial 1346.0023. E.F.F. is the co-owner of Fang-S Consultation AS (Organization number 931 410 717); he has an MTA with LMITO Therapeutics Inc (South Korea), a CRADA arrangement with ChromaDex (USA), a commercialization agreement with Molecule AG/VITADAO; he is a consultant to Aladdin Healthcare Technologies (UK and Germany), the Vancouver Dementia Prevention Centre (Canada), Intellectual Labs (Norway), MindRank AI (China), NYO3 (Norway and China), and Epivity Health (Norway). The other authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Distribution of z-scored CSF neopterin, tryptophan, kynurenines and KTR- and KA/QA ratios for men and women in the CU and AD groups. The split violin plots show the distribution, inserted box plots show the median (middle line), 1st quartile (lower box limit) and 3rd quartile (upper box limit). Abbreviations: AD: Alzheimer’s disease; KA/QA: kynurenic acid/quinolinic acid ratio; KTR: kynurenine/tryptophan ratio; CSF: cerebrospinal fluid; CU: cognitively unimpaired
Fig. 2
Fig. 2
Interaction between neopterin and sex on KA levels and the KA/QA ratio in AD. Marginsplot with 95% confidence intervals of predicted change in a) KA and b) KA/QA ratio for men and women across levels of z-scored neopterin ranging from three standard deviations below the mean to three standard deviations above the mean. The interaction is adjusted for main effects of sex and neopterin as well as age, CSF Aβ42 and CSF p-tau181 levels. Abbreviations: Aβ: amyloid-β; AD: Alzheimer’s disease; CSF: cerebrospinal fluid; KA: kynurenic acid; p-tau: phosphorylated tau; QA: quinolinic acid
See this image and copyright information in PMC

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