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Hydroxychloroquine lowers Alzheimer's disease and related dementias risk and rescues molecular phenotypes related to Alzheimer's disease Vijay R Varma^ 1 , Rishi J Desai^ 2 , Sheeja Navakkode^ 3 4 , Lik-Wei Wong^ 4 5 , Carlos Anerillas^ 6 , Tina Loeffler^ 7 , Irene Schilcher^ 7 , Mufaddal Mahesri^ 2 , Kristyn Chin^ 2 , Daniel B Horton^ 8 , Seoyoung C Kim^ 2 , Tobias Gerhard^ 8 , Jodi B Segal^ 9 , Sebastian Schneeweiss^ 2 , Myriam Gorospe^ 6 , Sreedharan Sajikumar^ 4 5 10 , Madhav Thambisetty^ 11 Affiliations Expand Affiliations * ^1 Clinical and Translational Neuroscience Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, USA. * ^2 Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. * ^3 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore. * ^4 Department of Physiology, National University of Singapore, Singapore, Singapore. * ^5 Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. * ^6 Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA. * ^7 QPS Austria GmbH, Parkring 12, 8074, Grambach, Austria. * ^8 Center for Pharmacoepidemiology and Treatment Science, Ernest Mario School of Pharmacy, Rutgers University, New Brunswick, NJ, USA. * ^9 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. * ^10 Life Sciences Institute Neurobiology Programme, National University of Singapore, Singapore, Singapore. * ^11 Clinical and Translational Neuroscience Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, USA. thambisettym@mail.nih.gov. * PMID: 36577843 * DOI: 10.1038/s41380-022-01912-0 Item in Clipboard Hydroxychloroquine lowers Alzheimer's disease and related dementias risk and rescues molecular phenotypes related to Alzheimer's disease Vijay R Varma et al. Mol Psychiatry. 2022. Show details Display options Display options Format [Abstract] Mol Psychiatry Actions * Search in PubMed * Search in NLM Catalog * Add to Search . 2022 Dec 28. doi: 10.1038/s41380-022-01912-0. Online ahead of print. Authors Vijay R Varma^ 1 , Rishi J Desai^ 2 , Sheeja Navakkode^ 3 4 , Lik-Wei Wong^ 4 5 , Carlos Anerillas^ 6 , Tina Loeffler^ 7 , Irene Schilcher^ 7 , Mufaddal Mahesri^ 2 , Kristyn Chin^ 2 , Daniel B Horton^ 8 , Seoyoung C Kim^ 2 , Tobias Gerhard^ 8 , Jodi B Segal^ 9 , Sebastian Schneeweiss^ 2 , Myriam Gorospe^ 6 , Sreedharan Sajikumar^ 4 5 10 , Madhav Thambisetty^ 11 Affiliations * ^1 Clinical and Translational Neuroscience Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, USA. * ^2 Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. * ^3 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore. * ^4 Department of Physiology, National University of Singapore, Singapore, Singapore. * ^5 Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. * ^6 Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA. * ^7 QPS Austria GmbH, Parkring 12, 8074, Grambach, Austria. * ^8 Center for Pharmacoepidemiology and Treatment Science, Ernest Mario School of Pharmacy, Rutgers University, New Brunswick, NJ, USA. * ^9 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. * ^10 Life Sciences Institute Neurobiology Programme, National University of Singapore, Singapore, Singapore. * ^11 Clinical and Translational Neuroscience Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, USA. thambisettym@mail.nih.gov. * PMID: 36577843 * DOI: 10.1038/s41380-022-01912-0 Item in Clipboard Cite Collections Display options Display options Format [Abstract] Abstract We recently nominated cytokine signaling through the Janus-kinase-signal transducer and activator of transcription (JAK/ STAT) pathway as a potential AD drug target. As hydroxychloroquine (HCQ) has recently been shown to inactivate STAT3, we hypothesized that it may impact AD pathogenesis and risk. Among 109,124 rheumatoid arthritis patients from routine clinical care, HCQ initiation was associated with a lower risk of incident AD compared to methotrexate initiation across 4 alternative analyses schemes addressing specific types of biases including informative censoring, reverse causality, and outcome misclassification (hazard ratio [95% confidence interval] of 0.92 [0.83-1.00], 0.87 [0.81-0.93], 0.84 [0.76-0.93], and 0.87 [0.75-1.01]). We additionally show that HCQ exerts dose-dependent effects on late long-term potentiation (LTP) and rescues impaired hippocampal synaptic plasticity prior to significant accumulation of amyloid plaques and neurodegeneration in APP/PS1 mice. Additionally, HCQ treatment enhances microglial clearance of Ab[1-42,] lowers neuroinflammation, and reduces tau phosphorylation in cell culture-based phenotypic assays. Finally, we show that HCQ inactivates STAT3 in microglia, neurons, and astrocytes suggesting a plausible mechanism associated with its observed effects on AD pathogenesis. HCQ, a relatively safe and inexpensive drug in current use may be a promising disease-modifying AD treatment. This hypothesis merits testing through adequately powered clinical trials in at-risk individuals during preclinical stages of disease progression. (c) 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply. References 1. 1. Cummings JL, Morstorf T, Zhong K. Alzheimer's disease drug-development pipeline: few candidates, frequent failures. Alzheimer's Res Ther. 2014;6:37. - DOI 2. 1. Yiannopoulou KG, Anastasiou AI, Zachariou V, Pelidou SH. Reasons for failed frials of disease-modifying treatments for Alzheimer disease and their contribution in recent research. Biomedicines. 2019;7:1-16. 3. 1. Desai RJ, Varma VR, Gerhard T, Segal J, Mahesri M, Chin K, et al. Targeting abnormal metabolism in Alzheimer's disease: The drug repurposing for effective Alzheimer's medicines (DREAM) study. Alzheimers Dement (N. Y). 2020;6:e12095. 4. 1. Nicolas CS, Amici M, Bortolotto ZA, Doherty A, Csaba Z, Fafouri A, et al. The role of JAK-STAT signaling within the CNS. JAKSTAT. 2013;2:e22925. 5. 1. Jain M, Singh MK, Shyam H, Mishra A, Kumar S, Kumar A, et al. Role of JAK/STAT in the neuroinflammation and its association with neurological disorders. 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