Kynurenine pathway dysregulation in cognitive impairment and dementia: a systematic review and meta-analysis

The kynurenine pathway (KP) might be involved in pathophysiological processes associated with dementia, but clinical studies reported contradictory results. This systematic review and meta-analysis summarized the available evidence for (i) differences in KP metabolites in patients with cognitive impairment compared to cognitively healthy individuals and (ii) associations between KP metabolites and cognitive functioning. English, full-length articles with prospective, cross-sectional, or case-control study designs, published in Pubmed, Embase, PsychINFO, or the Cochrane Database of Systematic Reviews up to October 2023, were included. Random-effects meta-analyses of standardized mean differences (SMD) were performed. Heterogeneity, meta-regression, small study bias, and study quality assessments were carried out. Of 8797 retrieved studies, 98 were eligible for the systematic review. Meta-analyses comparing Alzheimer's disease (AD) dementia patients to controls (n = 27 studies) indicated lower CSF levels of tryptophan (SMD = - 0.26 [95% CI - 0.41, - 0.12]), 3-hydroxykynurenine (- 0.21 [- 0.39, - 0.04]), anthranilic acid (- 0.28 [- 0.48, - 0.08]), and quinolinic acid (- 0.38 [- 0.56, - 0.21]) in AD dementia, while CSF levels of kynurenic acid were higher (0.18 [0.01, 0.35]). Blood levels of tryptophan (- 0.39 [- 0.51, - 0.28]), kynurenic acid (- 0.31 [- 0.47, - 0.15]), xanthurenic acid (- 0.34 [- 0.54, - 0.15]), and 3-hydroxyanthranilic acid (- 0.42 [- 0.61, - 0.22]) were lower in AD dementia. For some of these metabolites, similar directions were observed in meta-analyses comparing individuals with mild cognitive impairment with controls, although the number of included studies in these analyses was relatively small (n = 11). Associations with cognitive test scores were inconclusive and generally non-significant. These results suggest that AD dementia is associated with lower blood levels of several KP metabolites. Findings challenge current assumptions of neurotoxic quinolinic acid levels being associated with dementia.