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

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 Aβ1-42, 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.

Longitudinal progression of blood biomarkers reveals a key role of astrocyte reactivity in preclinical Alzheimer’s disease

“…Together with the observation that plasma GFAP levels are associated both with severity of AD pathology and manifestation of AD symptoms, they indicate that experimental treatments targeting reactive astrocytosis may be promising candidate AD therapies. We recently showed that the commonly used immune modulator drug hydroxychloroquine, inactivates STAT3, a key regulator of GFAP expression and ameliorates molecular abnormalities relevant to AD (47). Furthermore, we demonstrated that hydroxychloroquine rescues impaired hippocampal synaptic plasticity in the APP/PS1 mouse model of AD as well as reduces risk of incident AD in a large real world clinical dataset (47).…”

“…We recently showed that the commonly used immune modulator drug hydroxychloroquine, inactivates STAT3, a key regulator of GFAP expression and ameliorates molecular abnormalities relevant to AD (47). Furthermore, we demonstrated that hydroxychloroquine rescues impaired hippocampal synaptic plasticity in the APP/PS1 mouse model of AD as well as reduces risk of incident AD in a large real world clinical dataset (47). Monitoring plasma GFAP levels as a surrogate outcome measure in studies of experimental AD treatments may be a useful strategy to determine their potential utility as disease-modifying AD treatments.…”

LAX1 as a Core Biomarker in Alzheimer's Disease and Periodontitis via the STAT signaling pathway

“…Future research efforts may focus on gaining a deeper understanding of the molecular mechanisms of STAT in onset, development of Alzheimer's disease, exploring its roles in neuroinflammation, synaptic damage, and neuron survival [34]. Uncovering the functions of STAT in Alzheimer's disease may contribute to understanding the pathophysiology of the disease, provide targets for development of potential therapeutic strategies [35,36].…”

Immunological dimensions of neuroinflammation and microglial activation: exploring innovative immunomodulatory approaches to mitigate neuroinflammatory progression

“…Varma et al. ( 206 ) documented that hydroxychloroquine (HCQ) reduces the risk of AD and related dementias while also ameliorating molecular phenotypes associated with AD. In a study involving 109,124 rheumatoid arthritis patients receiving routine clinical care, the initiation of HCQ showed a decreased risk of incident AD compared to methotrexate initiation, addressing various biases through four alternative analysis schemes.…”