Administered early, an already approved drug may help stop Alzheimer’s progression
The Alzheimer's disease research community is in a great deal of flux at the moment. After a series of high-profile clinical trial failures, debate rages over whether the current causal hypothesis for the disease is correct. A new study has revealed novel insights into the early stages of the disease's development and suggests treatment may only be effective if delivered before a person becomes symptomatic.
For several decades the generally agreed hypothesis regarding the main symptomatic cause behind the degenerative effects of Alzheimer's disease was that the build-up of plaques, composed of a protein called beta-amyloid, resulted in the systematic destruction of neurons. But the big problem that has arisen is that almost all efforts to target this amyloid build up, in one way or another, have failed. An astounding 99.6 percent of clinical trials into drugs to help beat Alzheimer's have failed.
Attempting to better explain why amyloid-targeting drugs are failing in trials, some scientists are beginning to suggest the disease in the subjects in these trials may have progressed too far to respond effectively. Maybe instead of a curative agent, we need to be focusing on preventative agents?
"Based on what we've learned so far, it is my opinion that we will never be able to cure Alzheimer's disease by treating patients once they become symptomatic," says George Bloom, corresponding author on the latest study. "The best hope for conquering this disease is to first recognize patients who are at risk, and begin treating them prophylactically with new drugs and perhaps lifestyle adjustments that would reduce the rate at which the silent phase of the disease progresses."
The new research from the University of Virginia demonstrates that one of the key mechanisms preceding specific neuron cell death in the disease involves the movement of calcium through channels on cell surfaces. The scientists hypothesized that cell death could be prevented by closing a certain receptor that allows calcium to flow and ultimately cause neuronal destruction.
Furthermore, the study suggests that a currently used FDA-approved drug called memantine, may slow or prevent progression of the disease when administered before symptoms have appeared. Memantine is currently prescribed to treat patients with moderate to severe Alzheimer's disease, and it works by blocking the same receptor that the new research concludes as key to the progression of the disease.
"I don't want to raise false hopes," says Bloom, but "if this idea of using memantine as a prophylactic pans out, it will be because we now understand that calcium is one of the agents that gets the disease started, and we may be able to stop or slow the process if done very early."
Prior studies have shown that there isn't any clear evidence that memantine is of benefit to patients suffering from mild Alzheimer's disease. But, this new research points to the importance of developing treatments that are administered way before the disease has explicitly taken hold. Of course, this raises two fundamentally challenging hurdles that future research will need to overcome.
First, this hypothesis highlights a lack of clear diagnostic tools that can identify Alzheimer's disease before neurodegenerative cognitive symptoms have appeared. It's thought that the disease can take over a decade before it progresses to the point where cognitive degeneration becomes symptomatically visible. From PET scans, to smell and blood tests, a flurry of work is ongoing to identify early biomarkers of the disease, but nothing completely accurate has been confirmed as of yet.
The other problem this early preventative hypothesis faces is that it will potentially take decades of study before we can clearly confirm whether a preventative treatment is effective in humans. Targeting high-risk patients at younger ages with preventative treatments means any clinical trials will need significant long-term follow up data before a conclusion is made. If you can target high risk patients in their late 50s or early 60s for preventative trials, it really wouldn't be before those patients reach their 80s that you could draw a long-term conclusion.
The University of Virginia team is forging ahead, currently designing a human clinical trial into the efficacy of memantine as an early preventative agent against Alzheimer's.
The new research was published in the journal Alzheimer's & Dementia.
Source: University of Virginia