Lecanemab – a monoclonal antibody with the brand name Leqembi – was recently FDA approved for Alzheimer’s treatment based on evidence that it slows the disease’s progression.
Now, Vanderbilt University Medical Center researchers are probing the antibody’s potential for another, equally valuable application: preventing initial symptom onset.
The work is part of a worldwide clinical trial exploring whether lecanemab may prevent or delay symptoms in patients who have significant brain amyloid accumulation but are not yet showing signs of dementia.
The five-year trial, known as the AHEAD Study, involves about 50 centers worldwide. As with all prevention studies, a large dataset is needed to convincingly demonstrate benefit.
According to Paul Newhouse, M.D., Jim Turner Chair in Cognitive Disorders at Vanderbilt University Medical Center, the aim of AHEAD is to evaluate the drug’s use for “secondary prevention” of Alzheimer’s. A secondary prevention takes place when a mechanism that has begun is arrested, in contrast to primary prevention that addresses the issue at an earlier point.
Newhouse said the researchers are looking to determine “the right target and the right drug for the right stage of Alzheimer’s.”
A “Relentless” Disease
“People with high amounts of amyloid face a relentless downhill course of cognitive decline, even if they have no symptoms today,” Newhouse said.
These brain changes from the disease can appear a decade or more before symptoms arrive. By the time mild cognitive impairment is apparent, he says, substantial irreversible damage has likely occurred.
AHEAD of Memory Loss
Although no standardized test exists for pre-symptomatic Alzheimer’s, clinicians can detect amyloid, as well as tau, another potentially abnormal protein, in the blood. Blood tests can provide a probability score that an individual will show elevated brain amyloid in PET scan images of the brain.
“In the AHEAD study, we are recruiting individuals who are normal cognitively, who have no symptoms of memory loss,” Newhouse said. “If testing then indicates significant amyloid buildup, we can recommend that they consider participating in this trial.”
Participants are randomly assigned to receive either a biweekly infusion of the monoclonal antibody to remove the amyloid from the brain or a saline placebo.
Lecanemab does not stop amyloid production but works through an action Newhouse describes as “cleaning out the garbage.” By reducing the accumulation early and thoroughly enough, it may never create discernable problems, he said.
Amyloid buildup not only starts the Alzheimer’s pathology, it also creates a cascade of downstream effects.
“Amyloid damages nerve cells, which then secrete another toxic protein called tau, that spreads and eventually destroys those nerve cells,” the researcher said.
“We all make amyloid in our brains. Some people overproduce it. If we remove the amyloid substantially – and there is evidence that it has to be substantial – then we may stand a good chance of delaying the progression to dementia.”
Prevention and Risk Factors
The study could be a path to better understanding of Alzheimer’s development and ways to prevent it, Newhouse said.
“We want to introduce the idea of preventing disease rather than waiting for it. We want to get rid of the idea that becoming memory-impaired is a normal part of aging. We don’t think that is true.”
Genetics play a role in Alzheimer’s development, along with a number of other factors, some of which are not fully understood, Newhouse said.
“We want to get rid of the idea that becoming memory-impaired is a normal part of aging.”
“A strong family history may indicate the presence of a very reactive inflammatory or immune system. Higher levels of education, staying intellectually engaged, taking good care of yourself, exercising – while they can’t necessarily change the underlying biology, they can modify the risk.
“The important distinction could be not whether it accumulates, but what damage it does. And the bottom line is that having a head full of amyloid is just not a good thing.”
AHEAD is still recruiting patients, nationally and internationally. While there is a waiting list to join at Vanderbilt, openings periodically occur.
To refer a potential participant, email Blake Wilson at Blake.Wilson@vumc.org or call: 615-936-4997.
“We’re working hard to offer this to underrepresented communities by raising consciousness about the risk of dementia and about the possibility of prevention,” Newhouse said.