Table A1.

Differences of kynurenine pathways in the CNS and the periphery in Alzheimer’s disease.

Alzheimer’s Disease
In the CNS	Ref.	In the Periphery	Ref.
-Decreased KYNA in the CSF	[84]	-Increased KYN/TRP ratio (IDO activity) associated with reduced cognitive performance	[95]
-Increased KYNA in the putamen and caudate nucleus -Increased KAT I activities in both nuclei -Minor increased KAT II in the caudate nucleus -Marked increased KYNA in the caudate nucleus and putamen	[84]	-Decreased serum and red blood cell KYNA levels	[86]
-A β 1–42 induces production of QUIN by human macrophages and microglia	[143]	-Lower TRP and KYNA concentrations in plasma -Non-significant increase of KYN, 3-HK and AA levels, and a marked increase of QUIN -IncreaseKYN/TRp ratio which suggests increased IDO activity -Positive correlations between cognitive function tests and plasma KYNA levels, and inversely correlations between these tests and QUIN levels	[68]
-Enhanced IDO and QUIN immunoreactivity in the hippocampus in association with senile plaques	[56]	-Increased serum levels of 3-HK -No increases in other downstream KP metabolites -3-HK can be used as a biomarker (Schwarz et al., 2013)	[55]
- QUIN is co-localized with hyperphosphorylated tau within cortical neurons in AD brain -QUIN induces tau phosphorylation in human neurons	[57]	-Upregulation of serotonin pathway while downregulation of kynurenine pathway in AD transgenic mice urine	[144]
-Confirmed association of IDO-1 with senile plaques for the first time -IDO-1 specifically localized inconjunction with neurofibrillary tangles	[58]	-Decreased TRP, XA, 3-HAA and QUIN in plasma -KYN, AA, QUIN, and markers of immune activation increased with age, while XA decreased with age -Inflammation-related markers were associated with age, but not AD. -Elderly AD patients with high QUIN performed worse on the CamCog test	[61]
-Expression and cell distribution of TDO and QUIN, and their co-localization with neurofibrillary tangles and senile β amyloid deposition were also determined in hippocampal sections. -Higher TDO and IDO-1 immunoreactivity observed in the hippocampus -TDO co-localizes with QUIN, neurofibrillary tangles-tau and amyloid deposits in the hippocampus -TDO is highly expressed in the brains of AD mice and in AD patients, suggesting that TDO-mediated activation of the KP could be involved in neurofibrillary tangles formation and associated with senile plaque	[59]	-Elevated KYN, AA and 3-HK in serum in neocortical amyloid-β load (NAL+) versus NAL− females in preclinical AD -Observed positive correlation between NAL and the serum KP metabolite concentrations	[79]
-Higher KYNA and QUIN concentrations in CSF -This observation together with other TRP pathway intermediates were correlated with either CSF Amyloid β 1–42, or tau and phosphorylated Tau-181.	[60]	-Positive correlation between Neurofilament light chain (NFL) and IDO activity -Positive correlations between NFL and KYN, KYNA, 3-HK, AA and QUIN -Observed significant associations between plasma A β 40 and the KYN/TRP ratio, KYNA, KYNA, AA and QUIN -Significant associations between plasma A β 42 and the KYN/TRP ratio, kynurenic acid, anthranilic acid and quinolinic acid -On stratifying participants based on their NAL status, NFL correlated with KP metabolites irrespective of NAL status -But associations between plasma A β and KP metabolites were only pronounced in individuals with high NAL while associations in individuals with low NAL were nearly absent.	[145]
-Increased 3-HK/KYN ratio correlated with t-tau and p-tau in CSF	[98]	-Plasma concentrations of KYN, 3-HK, AA, PIC, and neopterin significantly correlated with their respective CSF levels -Plasma KYN and PIC inversely correlated with CSF p-tau and t-tau	[98]
-Higher KYNA concentration in CSF compared with healthy subjects or with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and progressive supranuclear palsy (PSP) -No significant differences in KYNA levels in CSF between any other neurodegenerative groups (FTD, ALS, PSP) and controls. -Increased KYNA concentration in CSF specific to AD.	[67]	-Plasma KYN positive associations with plasma NF-L levels, both, before and after adjusting for potential confounding variables (age, sex, APOE ε4, BMI) -Plasma KYN correlated significantly with plasma NF-L in Aβ+ participants and a trend level significance were observed in Aβ- participants.	[146]