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Hydroxychloroquine lowers dementia risk in humans, improves molecular signs of Alzheimer’s in mouse and cell models

Taking hydroxychloroquine (HCQ) is linked to lower rates of Alzheimer’s disease and related dementias in people with rheumatoid arthritis, according to an international team of researchers led by NIA scientists. The study, published in Molecular Psychiatry, also included mouse and cell models to show that HCQ can improve early molecular signs of Alzheimer’s by reducing inflammation and enhancing the clearance of abnormal buildup of proteins that form amyloid plaques and neurofibrillary tangles. Because HCQ is already FDA-approved for other health conditions, these new study results could lay a strong foundation for clinical trials to test HCQ in older adults who are at high risk of developing dementia.

Two researchers sit by microscope

Previously, NIA Drug Repurposing for Effective Alzheimer’s Medicines (DREAM) researchers identified that HCQ, a drug commonly prescribed to treat rheumatoid arthritis, was a promising option to treat dementia. Building on this potential, the research team studied a combination of insurance claims data, mouse models, and cell culture-based experiments. Looking at Medicare claims data from more than 100,000 rheumatoid arthritis patients with an average age of 74, they found that after two years of treatment, older adults who took HCQ to treat rheumatoid arthritis were 8% to 16% less likely to develop Alzheimer’s or a related dementia than those who took other drugs, such as methotrexate or leflunomide.

Next, the researchers tested whether HCQ could improve memory-forming mechanisms in a mouse model of Alzheimer’s. Synaptic plasticity is the process that allows neurons to communicate and form memories. In the Alzheimer’s mouse model, synaptic plasticity was impaired, but HCQ treatment restored synaptic plasticity completely. The researchers then tested whether HCQ could improve Alzheimer’s-related molecular changes in different types of cells grown in dishes in the lab. While results varied among cell types, the researchers found that HCQ could reduce the secretion of inflammatory molecules and improve the clearance of Alzheimer’s-related beta-amyloid protein and abnormal tau accumulation. The researchers also found that HCQ inactivates a protein called STAT3 in the mouse and cell models. They hypothesize that STAT3 inactivation may be responsible for the effects of HCQ in their studies.

Findings from this study support HCQ as a promising repurposed drug candidate for preventing dementia when administered to at-risk individuals before the onset of symptoms. The authors note that their cell and mouse model data is limited because these models, while useful, do not perfectly recreate the complexity of Alzheimer’s in humans. Future studies will examine the effects of HCQ on memory and thinking in mouse models and explore whether HCQ works specifically through inactivating STAT3 to reduce molecular signs of Alzheimer’s. An earlier small trial in patients with established Alzheimer’s symptoms done in 2001 did not improve the progression of symptoms.

This project is funded in part by the NIH National Institute on Aging. It relates to NIH’s AD+ADRD Research Implementation Milestone 7.B, “Initiate research programs for translational bioinformatics and network pharmacology to support rational drug repositioning and combination therapy from discovery through clinical development.”

Reference: Varma VR, et al. Hydroxychloroquine lowers Alzheimer’s disease and related dementias risk and rescues molecular phenotypes related to Alzheimer’s disease. Molecular Psychiatry. 2022. Epub Dec 28. doi: 10.1038/s41380-022-01912-0.

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