Hydroxychloroquine lowers Alzheimer’s disease and related dementias risk and rescues molecular phenotypes related to Alzheimer’s disease

Vijay R. Varma, Rishi J. Desai, Sheeja Navakkode, Lik-Wei Wong, Carlos Anerillas, Tina Loeffler, Irene Schilcher, Mufaddal Mahesri, Kristyn Chin, Daniel B. Horton, Seoyoung C. Kim, Tobias Gerhard, Jodi B. Segal, Sebastian Schneeweiss, Myriam Gorospe, Sreedharan Sajikumar & Madhav Thambisetty

Publication Date: 12/28/2022

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 Aβ_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.

Introduction

Advances in understanding the basic biology of Alzheimer’s Disease (AD) have not translated into effective treatments [1]. Traditional drug discovery approaches have focused on modifying either amyloid plaque or neurofibrillary tangle pathologies, which may be downstream events in a cascade that is initiated years before these pathologies appear. Therefore, identifying the earliest molecular abnormalities in disease progression may be key to developing effective treatments for AD. Equally importantly, there is growing consensus that pharmacological modulation of multiple key pathogenic pathways simultaneously may be preferable to agents against single targets [2].

We recently defined a hypothetical network of interacting and intersecting metabolic pathways in Alzheimer’s disease, linked to dysregulation in brain glycolysis- the Alzheimer’s Disease Aberrant Metabolism (ADAM) network [3]. We nominated genetic regulators of metabolic and signaling reactions in the ADAM network as plausible AD drug targets. Cytokine signaling through the Janus-kinase–signal transducer and activator of transcription (JAK/STAT) pathway was nominated as one such drug target for pharmacoepidemiologic analyses in the Drug Repurposing for Effective Alzheimer’s Medicines (DREAM) study [3]. Prior studies have suggested that dysregulation in this pathway may be associated with neurodegenerative diseases [4, 5] and may therefore may be a plausible therapeutic target [6,7,8]. We recently showed that disease modifying antirheumatic drugs (DMARDs) including tofacitinib (a JAK inhibitor), and 2) tocilizumab (an interleukin [IL]-6 inhibitor) were not associated with risk of AD and related dementias (ADRD) while TNF inhibitors may reduce risk of ADRD among patients with cardiovascular disease [9]. We additionally showed that C188-9, an experimental STAT3 inactivator currently in human clinical trials of cancer, rescued several molecular phenotypes relevant to AD in cell culture-based phenotypic assays [10].