Tryptophan Metabolism and Neurodegeneration: Longitudinal Associations of Kynurenine Pathway Metabolites with Cognitive Performance and Plasma Alzheimer’s Disease and Related Dementias Biomarkers in the Duke Physical Performance Across the LifeSpan Study

Article type: Research Article

Authors: Parker, Daniel C.^{a; b; *} | Kraus, William E.^{b; c; d; e} | Whitson, Heather E.^{a; b} | Kraus, Virginia B.^{b; d; e; f} | Smith, Patrick J.^g | Cohen, Harvey Jay^{a; b; e} | Pieper, Carl F.^{b; e; h} | Faldowski, Richard A.^h | Hall, Katherine S.^{b; e; i} | Huebner, Janet L.^{d; e} | Ilkayeva, Olga R.^{d; j; k} | Bain, James R.^{b; d; e; j; k} | Newby, L. Kristin^{c; l} | Huffman, Kim M.^{b; d; f}

Affiliations: [a] Duke University School of Medicine, Division of Geriatrics, Durham, NC, USA | [b] Duke University Center for the Study of Aging and Human Development, Durham, NC, USA | [c] Duke University School of Medicine, Division of Cardiology, Durham, NC, USA | [d] Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA | [e] Claude D. Pepper Older Americans Independence Center, Duke University School of Medicine, Durham, NC, USA | [f] Duke University School of Medicine, Division of Rheumatology and Immunology, Durham, NC, USA | [g] Department of Psychiatry, University of North Carolina, Chapel Hill, Chapel Hill, NC, USA | [h] Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USA | [i] Geriatric Research, Education, and Clinical Center, Veterans Affairs Medical Center, Durham, NC, USA | [j] Sarah W. Stedman Nutrition and Metabolism Center, Duke University School of Medicine, Durham, NC, USA | [k] Department of Medicine, Duke University School of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Durham, NC, USA | [l] Duke University Clinical and Translational Science Institute, Durham, NC, USA

Correspondence: [*] Correspondence to: Daniel Parker, MD, Box 3003, Duke University Medical Center, Durham, NC 27710, USA. Tel.: +1 919 660 7692; E-mail: [email protected].

Abstract: Background:The kynurenine pathway (KP) comprises a family of tryptophan-derived metabolites that some studies have reported are associated with poorer cognitive performance and an increased risk of Alzheimer’s disease and related dementias (ADRD). Objective:The objective of this study was to determine the associations of plasma KP metabolites (kynurenine [KYN], kynurenic acid [KA], and tryptophan [TRP]) with a panel of plasma ADRD biomarkers (Aβ42/ β40 ratio, pTau-181, glial fibrillary acidic protein [GFAP], and neurofilament light [NfL]) and cognitive performance in a subset of older adults drawn from the Duke Physical Performance Across the LifeSpan (PALS) study. Methods:The Montreal Cognitive Assessment (MoCA) was used to assess cognitive performance. We used multivariate multiple regression to evaluate associations of the KYN/TRP and KA/KYN ratios with MoCA score and plasma ADRD biomarkers at baseline and over two years (n = 301; Age = 74.8±8.7). Results:Over two years, an increasing KYN/TRP ratio was associated with increasing plasma concentrations of plasma p-Tau181 (β= 6.151; 95% CI [0.29, 12.01]; p = 0.040), GFAP (β= 11.12; 95% CI [1.73, 20.51]; p = 0.020), and NfL (β= 11.13; 95% CI [2.745, 19.52]; p = 0.009), but not MoCA score or the Aβ42/Aβ40 ratio. There were no significant associations of KA/KYN with MoCA score or plasma ADRD biomarkers. Conclusion:Our findings provide evidence that greater concentrations of KP metabolites are associated longitudinally over two years with greater biomarker evidence of neurofibrillary tau pathology (pTau-181), neuroinflammation (GFAP), and neurodegeneration (NfL), suggesting that dysregulated KP metabolism may play a role in ADRD pathogenesis.

Keywords: Alzheimer’s disease and related dementias, biomarkers, cognition, kynurenines, tryptophan

DOI: 10.3233/JAD-220906

Journal: Journal of Alzheimer's Disease, vol. 91, no. 3, pp. 1141-1150, 2023