One of the main hallmarks of Alzheimer’s disease is the accumulation of toxic protein clumps called amyloid-beta plaques inside the brain (for more detail see Alzheimer’s Disease: A General Overview). For the past several decades, the predominant theory among neuroscientists has been that these plaques are the main cause of the disease, and that removing them is the key to a cure. This is known as the amyloid cascade hypothesis.
A recent study published in Nature, one of the world’s premier scientific journals, reported promising results from a phase 1b clinical trial of a new drug called aducanumab. This drug works by selectively targeting amyloid-beta aggregates and marking them for destruction by the body’s immune system, an approach known as immunotherapy. The researchers demonstrated using mice that the drug is able to penetrate the blood-brain barrier and reduce levels of amyloid-beta plaques.
Various doses of the drug were injected into patients with mild Alzheimer’s disease once per month for one year. PET scans showed that the 125 subjects who completed the trial had reduced amyloid-beta levels in their brains compared to controls who were given a placebo. This reduction was enhanced the longer the drug was administered and the higher the dose. The subjects given the drug also had higher scores on tests of cognitive function. Notably, the drug slowed but did not prevent or reverse cognitive decline in these subjects, and the effects varied substantially based on the dosage.
Dozens of previous immunotherapeutic drug candidates for Alzheimer’s disease have failed early in clinical trials, and so these positive results are very exciting. However, this drug is far from being declared a cure, and there are several important caveats to keep in mind.
Problematic side effects have plagued Alzheimer’s drug trials for decades, and unfortunately this one was no exception. Nearly 25% of the subjects withdrew from the trial due to side effects, which included headache, urinary tract infection, upper respiratory infection, and an interesting phenomenon known as amyloid-related imaging abnormalities (ARIA). ARIA are small abnormalities that appear on MRI scans and are believed to be the result of cerebral microhemorrhages (“mini-strokes”). ARIA is a common side affect of amyloid-beta immunotherapy and is considered to be a serious condition. 41% of subjects given the highest dose of aducanumab experienced ARIA, compared to zero controls. Several subjects were also diagnosed with another type of serious hemorrhaging called superficial siderosis of the central nervous system. No deaths due to side effects were reported.
Additionally, it’s important to note that all of the subjects in the study were only in the earliest stages of Alzheimer’s disease, so it’s not clear how well this drug will work with patients in later stages. The trial was also relatively short-term and only in phase 1b. It’s not uncommon for drugs to succeed in early clinical trials but fail when they reach the final phase 3 trials, which is was happened with a promising Alzheimer’s drug candidate earlier this year.
The final point I want to make is that the success of aducanumab hinges on the amyloid cascade hypothesis being correct. The theory was considered dogmatic for years, but lately it has been experiencing scrutiny, due in large part to the discovery that nearly 1 in 3 elderly people have high levels of amyloid-beta in their brains despite being cognitively normal (for a deeper look at this controversy, see Where’s our cure to Alzheimer’s disease?). Though the majority of mainstream neuroscientists still support the amyloid cascade hypothesis, it’s important to keep its criticisms in mind. The scientific community will wait with bated breath for the drug’s phase 3 trial results.