Our paper, recently published in Molecular Psychiatry, suggests that hydroxychloroquine (HCQ), a relatively safe and inexpensive drug in current use, may be a promising disease-modifying Alzheimer’s disease (AD) treatment. The recent controversy around hydroxychloroquine’s use as a treatment for COVID-19 notwithstanding, the drug’s storied past and almost four centuries old history as a therapy for multiple diseases is a fascinating backdrop to our research.
A brief history
Hydroxychloroquine’s origin began in Chile prior to European occupation where Incan herbalists may have used the powdered bark from the quina tree, later named the Cinchona tree, to combat shivering due to fever. In 1638, during the Spanish occupation of the South Americas, pharmaceutical lore suggests that the wife of the Viceroy of Peru, Ana de Osorio, Countess of Chinchon acquired malaria and was successfully treated by a curanderos cure. This miracle treatment was imported to Europe by the Loyola Order of Jesuits where it became known, among other nicknames, as Jesuit’s powder.
By the end of the 17th century, the powdered bark from the quina tree became a staple of European apothecaries and was used almost universally to treat malarial fevers. Through the 18th century, Andean forests remained the only source of the bark and with the assistance of indigenous people, the Spanish ramped up production leading to almost complete depletion of natural supply.
In 1820, almost two centuries after the Incan herb was introduced to Europe, Pierre Joseph Pelletier and Joseph Bienaim Caventou established a factory in France to extract quinine from the bark. By the late 19thcentury, the British had smuggled seedlings from Peru and established groves in India and invented the gin and quinine tonic as an antimalarial for the colonial juggernaut as it expanded into India and Africa.
During World War II due to challenges accessing quina tree groves, quinacrine was synthesized, followed by chloroquine in 1934 and then HCQ in 1946, considered a safer alternative to chloroquine.
One drug: many discoveries
Prior to the European colonization of the South Americas, the bark of the quina tree was used for a number of ailments before it was used to treat malaria once European colonizers introduced the parasite to the region. In 1894, quinine was first repurposed to treat lupus, suggesting therapeutic benefits in autoimmune diseases. During World War II when the drug was used to treat malaria among troops fighting in the Pacific, it was noticed that servicemen with autoimmune conditions including inflammatory arthritis who took quinacrine or chloroquine experienced improvement. Since then the drug has been shown to be potentially efficacious across a number of different conditions including HIV. More recently, hydroxychloroquine is being tested in clinical trials in multiple cancers.
Our paper, in Molecular Psychiatry, suggests that HCQ may be a novel disease-modifying treatment in individuals at-risk of Alzheimer’s disease (AD) prior to the onset of symptoms. We conducted multiple experiments to test whether HCQ can impact AD: First we followed individuals taking HCQ for rheumatoid arthritis (RA) compared to individuals taking methotrexate or leflunomide (other drugs prescribed for RA) and found that those on HCQ had a lower risk of AD and other dementias. Second, we found that the drug corrected abnormalities in signaling between neurons in the hippocampus of a transgenic mouse model of AD.
Third, we found that HCQ reduces neuroinflammation, and increases clearance of amyloid-beta by specialized scavenger cells called microglia present in the brain. It also reduced the phosphorylation of tau protein, one of the key molecular events leading to the accumulation of neurofibrillary tangles in AD. Finally we showed that a plausible mechanism for these findings is the inactivation of STAT3, a protein that plays key roles in inflammation, autoimmune diseases, and cancer.
Our findings should be considered in the context of one small prior clinical trial examining the effect of HCQ on the progression of AD.
In 2001, the Lancet published findings from an 18-month randomized, clinical trial of 155 patients with early dementia (77 treated with HCQ and 78 with placebo). While these findings did not show any slowing of cognitive decline by HCQ after 18 months, there are a number of methodologic concerns to be considered. First, the trial likely had too few participants to show a difference in cognitive outcomes (i.e., underpowered). It is important to note that recent phase 2/3 clinical trials of experimental AD treatments including non-amyloid targeting drugs have recruited substantially higher numbers of patients (for example, see trial details for Semaglutide, Lecanemab, and ANAVEX2-73). Second, it takes about six months of therapy for HCQ to reach its steady-state concentration. A recent HCQ trial in multiple sclerosis that demonstrated clinical benefit of HCQ underscored the importance of prolonged dosing in patients. This important pharmacokinetic characteristic of the drug was not considered in the 2001 trial design. Additionally, our findings, which show that HCQ-associated lowering of AD risk emerges after approximately 2 years of treatment, further suggest the importance of prolonged dosing. Finally, the 2001 trial was performed prior to the routine use of PET imaging and/or CSF biomarkers to confirm a clinical diagnosis of AD- an important safeguard against inaccuracy of clinical diagnosis alone to screen and enroll eligible patients into trials of experimental AD treatments.
In summary, there is an urgent need to develop safe, effective, and easily accessible treatments for AD, which is a global public health challenge. Our research suggests that HCQ, an inexpensive, relatively safe and FDA-approved immune modulating drug in common use may benefit patients in early stages of AD by impacting multiple molecular pathways involved in the disease. These findings merit timely confirmation in adequately powered human clinical trials.
About the authors:
Vijay Varma is a staff scientist in the Clinical and Translational Neuroscience Section (CTNS) of the National Institute on Aging (NIA), Intramural Research Program (IRP). He received a PhD from the Johns Hopkins University Bloomberg School of Public Health. Madhav Thambisetty is a neurologist, senior investigator, and Chief of the CTNS, NIA IRP
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