There’s a long-running debate over the cause of Alzheimer’s disease. Just last week, we reported on a breakthrough regarding the in-development drug BAN2401 that appears to weigh heavily in favor for one side of the debate. This debate is important, too, for will contest lawyers searching for evidence of testamentary capacity during inheritance disputes. 

The crux of the debate is the “amyloid hypothesis,” a theory claiming that Alzheimer’s gradual degradation of the brain is caused by sticky plaques. The new drug, pioneered by Biogen and Eisai,  is designed to prevent these amyloid plaques from building up and attacking the clusters that have formed. To those on the believers’ side, this development affirms the link between plaques and mental degradation. 

However, for those on the other side of the debate, like Baird biotech analyst Brian Skorney, the medical trial was full of contradictory elements that make him wary of drawing positive conclusions. “The results are a mess,” Skorney said in a Scientific American article. “Not so much that they indicate an outright failure of the [amyloid] hypothesis, but they don’t really say anything informative at all.” 

To recap, in the drug trial, all tested doses had a significant effect on plaques as measured by a brain scan, and the more BAN2401 patients received, the less amyloid build-up they had after 18 months. However, when examining cognition, only those that received the highest dose showed a decrease in mental decline as compared to the placebo group. In fact, some patients who received low doses actually declined faster than those who received no treatment at all. 

It is these contradictory details that give skeptics the greatest ammunition. The question is then posed, if amyloid truly is the cause of Alzheimer’s, why didn’t each reduction in plaques lead to improved cognition? 

One of the key supporters of the amyloid theory, Dr. Al Sandrock, Biogen’s chief scientific officer, believes there is most likely a threshold of amyloid reduction that must be reached before patients can experience a benefit. This explains why the low doses saw decline. These dosages simply may not have hit that threshold.  

BAN2401 has received the greatest praise for its dual results: reducing amyloid and improving patient’s clinical results. Yet even these positive results have driven some of its greatest criticism.  

In the trial, about 70% of patients receiving the placebo had a genetic mutation that triples the risk of Alzheimer’s. But for those in the high dose group, just 30% of patients had the mutation, called APOE4.  The APOE4 mutation also reputedly has an important interaction with amyloid. The smaller number of APOE4 positive patients could explain why BAN2401 outperformed a saline injection in the high-dose group, naysayers say. Past trials suggest that APOE4 carriers have a more rapidly progressing Alzheimer’s than patients that don’t have the mutation. 

Could this mean that the drug’s potential as a solution and treatment for Alzheimer’s could just be smoke and mirrors?  

When we take a closer look at all the contradictions in this singular case then we can garner a greater understanding for why it is such a complicated and lengthy process for drugs to treat Alzheimer’s to come onto the market. It could take many years, decades even, before we might solidly see a marketable pharmacological breakthrough in Alzheimer’s prevention and treatment. In the meantime, doctors and drug companies continue their quest and all understand that time is of the essence.  To read more about the Amyloid Hypothesis, check out “The Amyloid Hypothesis of Alzheimer’s Disease at 25 Years,” by Dennis J. Selkoe, John Hardy.   



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