Hydroxychloroquine lowers Alzheimer's disease and related dementias risk and rescues molecular phenotypes related to Alzheimer's disease.
Vijay R VarmaRishi J DesaiSheeja NavakkodeLik-Wei WongCarlos AnerillasTina LoefflerIrene SchilcherMufaddal MahesriKristyn ChinDaniel B HortonSeoyoung C KimTobias GerhardJodi B SegalSebastian SchneeweissMyriam GorospeSreedharan SajikumarMadhav ThambisettyPublished in: Molecular psychiatry (2022)
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.
Keyphrases
- rheumatoid arthritis patients
- clinical trial
- healthcare
- cardiovascular disease
- disease activity
- cognitive decline
- lps induced
- spinal cord
- rheumatoid arthritis
- traumatic brain injury
- neuropathic pain
- high throughput
- high dose
- emergency department
- randomized controlled trial
- drug induced
- risk assessment
- combination therapy
- adipose tissue
- clinical practice
- quality improvement
- pain management
- chronic pain
- cognitive impairment
- climate change
- blood brain barrier
- systemic lupus erythematosus
- tyrosine kinase
- open label
- mild cognitive impairment
- human health
- single cell