Ì첩ÌåÓý

Scientists are taking aim at plaques, proteins, and inflammation to prevent or slow disease progression.

When the FDA approved the Alzheimer’s medication aducanumab (Aduhelm) in June 2021, it set off a firestorm of criticism. Some doctors and their patients cele­brated the decision, hailing the arrival of the first Alzheimer’s treatment in almost 20 years. The treatment is designed to reduce beta-­amyloid in the brain — clumps or plaques of the amyloid-beta protein, a hallmark of Alzheimer’s disease.

Other doctors felt the medication was rushed to market without enough evidence that the drug’s removal of amyloid plaques reversed cognitive decline. They also expressed concerns about the drug’s steep price tag ($56,000 per year), potential side effects of brain swelling and bleeding, and the frequent brain scans required for follow-up. Remarkably, the skeptics included a panel of experts convened to advise the FDA on whether to approve the drug. It is unusual for the FDA to approve a drug against the advice of the experts it has consulted.

Details of how aducanumab might be distributed, administered, and covered by insurance are still being hashed out. And the FDA wants a new nine-year trial to confirm that the drug works.

Aducanumab is just one drug with the potential to treat Alzheimer’s disease. Here are some others, including some being studied at Harvard.

Monoclonal antibodies

Monoclonal antibodies for Alzheimer’s (such as aducanumab) are lab-made antibodies designed to stick to amyloid. This signals the immune system to remove the amyloid. There are two types of these drugs.

One type targets soluble amyloid-beta (protein fragments that haven’t yet formed into plaques). Clinical trials of one, solanezumab, began in 2014. But by 2016, headlines noted that the drug failed in people with dementia. "We don’t think it failed as much as we were too late in the disease process. So we quadrupled the dose and we’re trying solanezumab in people ages 65 to 86 with amyloid but no dementia symptoms. We’ll get results in 2023," says Dr. Reisa Sperling, lead researcher and director of the Center for Alzheimer Research and Treatment at Harvard-affiliated Brigham and Women’s Hospital.

The other type of monoclonal antibody targets insoluble amyloid, which has already formed plaques. (Aducanumab is in this group.) Dr. Sperling is on the team investigating another such drug, lecanemab, in people ages 55 to 80 with either intermediate or high levels of amyloid plaques but no symptoms of Alzheimer’s. "We’re dosing people on the basis of how much amyloid we see on brain images," Dr. Sperling says, "and the earlier we start, the more chance we may have to prevent the symptoms of Alzheimer’s disease."

Other examples of monoclonal antibodies targeting insoluble amyloid-beta include donanemab and gantenerumab, both of which are now in clinical trials.

Gamma-secretase modulators

The body produces amyloid-beta by cutting it out from larger precursor proteins. "Amyloid precursor proteins are like a long piece of rope; amyloid-beta is a small section in the middle of the rope. You have to cut the long rope twice to get the amyloid-beta section out. The first cut is made by an enzyme called beta-secretase; the second is made by gamma-secretase," explains researcher Rudolph Tanzi, who directs the Genetics and Aging Research Unit and co-directs the Henry and Allison McCance Center for Brain Health at Harvard-affiliated Massachusetts General Hospital (MGH).

Experimental drugs called gamma- and beta-secretase inhibitors interfere with the cutting process and thereby reduce the amount of amyloid-beta produced. Unfortunately, several were found to be unsafe. So Tanzi is trying a different approach. "At MGH we are making gamma-secretase modulators that do not inhibit gamma-secretase but instead change where the second cut is made — another way of reducing the amount of amyloid-beta produced. We are aiming at a clinical trial to assess safety over the coming year," Tanzi says.

Additional approaches

Some experimental drugs target other aspects of the Alzheimer’s disease process.

Preventing tau tangles. Abnormal tau proteins are another hallmark of Alzheimer’s disease. They stick together and turn into fibrous tangles inside brain cells, killing the cells. Many researchers believe amyloid triggers the accumulation of tau. "Once you hit a certain level of amyloid, we think there may be an explosion of tau tangles, which we call the ‘cataustrophe,’" Dr. Sperling says. Experimental medications and vaccines to keep tau from tangling are being studied around the world, though not in large trials.

Stopping inflammation. Tanzi agrees that treatments targeting amyloid and tau may prove valuable if they’re started before Alzheimer’s symptoms emerge. After symptoms appear, however, he thinks that treatments targeting brain inflammation (neuroinflammation) have the most promise. "Our lab discovered the first Alzheimer’s disease neuroinflammation gene in 2008, and there is an ongoing clinical trial to block that gene. Another company has made a drug combination, called AMX035, that also protects neurons against neuroinflammation. It has already proved beneficial in a trial to treat ALS [amyotrophic lateral sclerosis, or Lou Gehrig’s disease] run by MGH and is now being considered for approval. It is currently being tested in an Alzheimer’s clinical trial at MGH as well." Other scientists are also developing drugs that target inflammation. None is in a large-scale trial yet.

Keys to success

Will any of these experimental medications be the breakthrough treatment we’ve been waiting for? It’s too early to tell. Experts are still debating whether the recently approved drug aducanumab will even be effective.

What’s becoming clear to many researchers is that we need to treat brain changes as early as possible in the Alzheimer’s disease process, before there’s a large buildup of plaques, tangles, and inflammation. "The disease pathology begins silently, a decade or two before symptoms appear, like cholesterol in heart disease. We don’t wait for someone to have a heart attack before we treat a high cholesterol level; we lower it earlier in life. That’s what we have to do with Alzheimer’s," Tanzi says.

And it may take a number of approaches to do the job. "I think anti-amyloid drugs might help somewhat in very mild dementia, but we likely need combination therapy once people have significant symptoms," Dr. Sperling says. "I feel positive we’re going in the right direction."

Rose Lincoln | Harvard University