Abstract | BACKGROUND: Depressive symptoms in Alzheimer's disease (AD) predict worse cognitive and functional outcomes. Both AD and major depression inflammatory processes are characterized by shunted tryptophan metabolism away from serotonin (5-HT) and toward the neuroinflammatory kynurenine (Kyn) pathway. The present study assessed associations between Kyn and behavioral, neuroanatomical, neuropathological, and physiological outcomes common to both AD and negative affect across the AD continuum. METHODS: RESULTS: A higher Kyn/ Tryptophan ratio was linked to many inflammatory markers, as well as lower functional independence and memory scores. A higher Kyn/5-HT ratio showed similar associations, but also strong relationships with negative affect and neuropsychiatric disturbance, executive dysfunction, and global cognitive decline. Further, gray matter atrophy was seen in hippocampus, anterior cingulate, and prefrontal cortices, as well as greater amyloid and total tau deposition. Finally, using moderated-mediation, several pro-inflammatory factors partially mediated Kyn/5-HT and negative affect scores in participants with subclinical Aβ (i.e., Aβ-), whereas such associations were fully mediated by Complement 3 in Aβ+ participants. CONCLUSION: These findings suggest that inflammatory signaling cascades may occur during AD, which is associated with increased Kyn metabolism that influences the pathogenesis of negative affect. Aβ and the complement system may be critical contributing factors in this process.
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Authors | Auriel A Willette, Colleen Pappas, Nathan Hoth, Qian Wang, Brandon Klinedinst, Sara A Willette, Brittany Larsen, Amy Pollpeter, Tianqi Li, Scott Le, Ana D Collazo-Martinez, Jonathan P Mochel, Karin Allenspach, Robert Dantzer, Alzheimer's Disease Neuroimaging Initiative |
Journal | Brain, behavior, and immunity
(Brain Behav Immun)
Vol. 95
Pg. 216-225
(07 2021)
ISSN: 1090-2139 [Electronic] Netherlands |
PMID | 33775832
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Copyright | Copyright © 2021 Elsevier Inc. All rights reserved. |
Chemical References |
- Amyloid beta-Peptides
- Kynurenine
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Topics |
- Alzheimer Disease
- Amyloid beta-Peptides
- Cognitive Dysfunction
- Humans
- Inflammation
- Kynurenine
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