Alzhiemer’s, the most common form of dementia, is increasingly prevalent. Estimates from the Alzheimer’s Association place the number of Americans suffering from Alzheimer’s and aged 65 and older, at 6.9 million.  Seventy-three percent of Alzheimer’s sufferers are aged 75 or older. Alzheimer’s prevalence is expected to rise to 11.2 million by 2040 and 12.7 million by 2050. Yet, even as the economic and social cost of Alzheimer’s rises, alongside advances in what we know about the disease, effective treatments for Alzheimer’s have not been found. Furthermore, novel treatments that defy consensus have failed to receive significant funding. One of those is the arthritis drug, hydroxychloroquine, known to many for erroneous claims about how it could treat Covid-19. Nevertheless, research suggests that it could be the cure to Alzheimer’s, but a consensus around the amyloid hypothesis is slowing down progress to coming to a definitive answer. 

Researchers typically focus on modifying either amyloid plaque or neurofibrillary tangle pathologies, as they pursue drug treatment. However, these events occur downstream from when the cascading process began. Researchers behind a December 2022 paper, “Hydroxychloroquine lowers Alzheimer’s disease and related dementias risk and rescues molecular phenotypes related to Alzheimer’s disease”, hypothesized that “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”. They identified the JAK/STAT pathway as a biological pathway that might be involved in Alzheimer's disease They observed that hydroxychloroquine can inactivate a part of this pathway, specifically STAT3, and wondered if hydroxychloroquine could affect the development and risk of Alzheimer's. They looked at data from 109,124 patients with rheumatoid arthritis who were receiving routine clinical care. They compared patients who started taking hydroxychloroquine with those who started taking methotrexate. The study found that starting  hydroxychloroquine was associated with a lower risk of developing Alzheimer’s compared to starting methotrexate. This was consistent across four different types of analyses designed to address various biases, such as patients stopping treatment for different reasons, the possibility that early symptoms of Alzehimer’s led to the choice of treatment, and errors in diagnosing Alzheimer’s. The hazard ratios (which measure risk) were all less than 1, indicating a reduced risk. The researchers also conducted experiments on mice genetically modified to develop Alzheimer’s. They found that  hydroxychloroquine improved brain functions related to memory (long-term potentiation), prevented brain changes associated with Alzheimer’s, and reduced the buildup of harmful proteins (amyloid plaques) and inflammation in the brain. 

Dr. Madhav Thambisetty, one of the authors of the paper and a neurologist at the National Institute on Aging, spoke to the New York Times this has not translated to significant funding or scientific support. The amyloid hypothesis, which holds that amyloid-β peptide is the causative agent in Alzheimer’s, remains the the most accepted model in the field. The hypothesis, which is over thirty years old, led researchers to theorize that if they removed  amyloid from the brain, they could stop or reverse the onset of Alzheimer’s. that process. Despite this, anti-amyloid drugs have failed to do so, with one critical review noting that, “...while Aβ may contribute to disease, genetic, clinical, imaging and biochemical data suggest a more complex aetiology. …the treatments have either no or uncertain clinical effect on cognition.” 

Is hydroxychloroquine the cure to Alzheimer’s? It’s impossible to tell without further testing. The research done by Thambisetty and his colleagues has three limitations which they note and want to overcome: firstly, they used various types of cell cultures to study how hydroxychloroquine affects different aspects of Alzheimer's. However, these cell-based tests only capture small parts of the disease and don't fully represent the complex interactions between genes and the environment that occur in older adults; secondly, in their mouse studies, they did not measure cognitive functions, like memory and learning. Even though the study on human patients suggests hydroxychloroquine might have clinical benefits, it would be helpful to have data from animal models showing how it affects behavior and cognition; and thirdly, the experiments investigating how hydroxychloroquine might work by inactivating STAT3 are still in the early stages. The results suggest that hydroxychloroquine could affect Alzheimer’s through this mechanism, but further studies are needed to confirm this. So, while the study shows promising results, it has some limitations: it doesn't fully replicate the complexity of Alzheimer’s in humans, lacks cognitive data from animal models, and the proposed mechanism of action needs more research. Unfortunately, given the strong consensus around the amyloid hypothesis and what the best course of drug discovery is, Thambisetty is uncertain when or if we will ever know if hydroxychloroquine is the answer to the problem of Alzheimer’s.