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      A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment

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          The locus coeruleus (LC) is the initial site of Alzheimer’s disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration in dementia. LC dysfunction contributes to Alzheimer’s pathobiology in experimental models, which can be rescued by increasing norepinephrine (NE) transmission. To test NE augmentation as a potential disease-modifying therapy, we performed a biomarker-driven phase II trial of atomoxetine, a clinically-approved NE transporter inhibitor, in subjects with mild cognitive impairment due to Alzheimer’s disease.

          The design was a single-center, 12-month double-blind crossover trial. Thirty-nine participants with mild cognitive impairment (MCI) and biomarker evidence of Alzheimer’s disease were randomized to atomoxetine or placebo treatment. Assessments were collected at baseline, 6- (crossover) and 12-months (completer). Target engagement was assessed by CSF and plasma measures of NE and metabolites. Prespecified primary outcomes were CSF levels of IL1α and Thymus-Expressed Chemokine. Secondary/exploratory outcomes included clinical measures, CSF analyses of Aβ42, Tau, and pTau181, mass spectrometry proteomics, and immune-based targeted inflammation-related cytokines, as well as brain imaging with MRI and FDG-PET.

          Baseline demographic and clinical measures were similar across trial arms. Dropout rates were 5.1% for atomoxetine and 2.7% for placebo, with no significant differences in adverse events. Atomoxetine robustly increased plasma and CSF NE levels. IL-1α and Thymus-Expressed Chemokine were not measurable in most samples. There were no significant treatment effects on cognition and clinical outcomes, as expected given the short trial duration. Atomoxetine was associated with a significant reduction in CSF Tau and pTau181 compared to placebo, but not associated with change in Aβ42. Atomoxetine treatment also significantly altered CSF abundances of protein panels linked to brain pathophysiologies, including synaptic, metabolism, and glial immunity, as well as inflammation-related CDCP1, CD244, TWEAK, and OPG proteins. Treatment was also associated with significantly increased BDNF and reduced triglycerides in plasma. Resting state fMRI showed significantly increased inter-network connectivity due to atomoxetine between the insula and the hippocampus. FDG-PET showed atomoxetine-associated increased uptake in hippocampus, parahippocampal gyrus, middle temporal pole, inferior temporal gyrus, and fusiform gyrus, with carry-over effects six months after treatment.

          In summary, atomoxetine treatment was safe, well tolerated, and achieved target engagement in prodromal Alzheimer’s disease. Atomoxetine significantly reduced CSF Tau and pTau, normalized CSF protein biomarker panels linked to synaptic function, brain metabolism, and glial immunity, and increased brain activity and metabolism in key temporal lobe circuits. Further study of atomoxetine is warranted for repurposing the drug to slow Alzheimer’s disease progression.

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          Oxford University Press (OUP)
          December 17 2021
          December 17 2021
          [1 ]Goizueta Alzheimer’s Disease Research Center, Emory University, Atlanta, Georgia, 30322, USA
          [2 ]Department of Neurology, Emory University, Atlanta, Georgia, 30322, USA
          [3 ]Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia, 30322, USA
          [4 ]Department of Biostatistics, Emory University, Atlanta, Georgia, 30322, USA
          [5 ]Department of Biochemistry, Emory University, Atlanta, Georgia, 30322, USA
          [6 ]Department of Human Genetics, Emory University, Atlanta, Georgia, 30322, USA
          [7 ]Department of Physiology, Emory University, Atlanta, Georgia, 30322, USA
          [8 ]NINDS, NIH, Bethesda, MD, 20892, USA
          [9 ]Tri-institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS), Georgia State University, Georgia Institute of Technology, Emory University, Atlanta, GA, 30303, USA
          [10 ]Department of Neurology and Knight ADRC, Washington University, St. Louis, MO, 630130, USA
          [11 ]Department of Neurosciences and ADRC, UCSD, San Diego, CA, 92093, USA
          © 2021




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