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If you dose high enough it might work, but are you stopping neurodegeneration? That’s why the real focus has been on other systems.”
To date, higher doses of cholinergic drugs, as Friedman alludes to, haven’t been possible because of their side effects such as debilitating nausea and vomiting.
“We simply cannot dose high enough on donepezil,” says Snyder, using the generic name for Aricept. “The top dose is typically 10 mg per day, which is likely at the low end of the therapeutic range, but if we go much higher in dose this leads to reduced tolerability.”
ALLEVIATING BRAIN ATROPHY?
One example of more sophisticated technology opening new windows came recently from Hampel. He and colleagues recently published a randomized, double-blinded study of prodromal patients—those who show cognitive symptoms but not dementia—who took 10mg a day of donepezil for 12 months. They had more reduction in the brain atrophy that is common to Alzheimer’s disease. They were compared to patients who took a placebo. Less atrophy seems like cold comfort, and it is far from proof that this type of drug can change the course of the disease. But Hampel calls it a “significant effect” and one of a few “robust and valid biomarkers,” or biological signals, that cholinergic intervention could have a disease-modifying effect.
The workgroup’s call to action also emphasizes the need for a more holistic approach. They say the pendulum should not swing fully toward the cholinergic system, or any one part of the brain. As with cancer, combinations of therapies will likely be necessary. “The continuation of the traditional search for magic bullets or ‘one-size-fits-all’ drugs will not likely succeed” in treating the most common form of Alzheimer’s, the authors write.
Their paper was in fact funded by Axovant, which the authors say had no influence on the content. But other high-profile figures in the field are advocates for more aggressive exploration of the cholinergic system as a bad actor in Alzheimer’s.
Now with Roche, Doody has pushed back against the amyloid-or-bust mentality for years. Until recently she was a top neurologist at Baylor College of Medicine in Houston and director of its Alzheimer’s Disease and Memory Disorders Center. In a 2016 interview with Xconomy, Doody criticized academics and the press for a dismissive attitude toward cholinergic drugs: “There’s a tremendous amount of nihilism.”
“It’s clear that disruption of the cholinergic system is tied to the symptoms and to the areas of brain where Alzheimer’s starts,” she says now. “Don’t ignore the cholinergic system. It’s a target.”