Alzheimer’s Drug Targets Disease Before Symptoms

In Alzheimer’s disease, changes in the brain can begin long before memory loss becomes noticeable. A new study suggests that very early intervention, from the “silent” stages of the disease, could reduce processes that occur before cognitive decline.

An experimental drug, developed at Northwestern University, shows potential as a treatment approach in the very early stages of Alzheimer’s disease.

In a new study, researchers they reported the identification of a previously unrecognized subtype, described as “highly toxic”, of beta-amyloid oligomers – toxic clumps of peptides. The team says this subtype appears to contribute to triggering some of the early problems associated with Alzheimer’s, including neuronal dysfunction, inflammation in the brain and activation of immune cells.

The investigational compound, a small molecule called NU-9, lowered the levels of this toxic subtype of beta-amyloid oligomers and significantly reduced its harmful effects in a mouse model of Alzheimer’s disease.

The researchers believe that by targeting these early changes at the very onset of the disease, NU-9 could prevent or considerably slow down the chain of events that, over time, leads to neuronal death. Overall, the results point to a possible way to attack Alzheimer’s in its early stages, before cognitive decline and other disabling symptoms set in.

The study was published on December 18, in Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association.

Corresponding author of the study, William Klein, professor of neurobiology at the Weinberg College of Arts and Sciences, is also a co-founder of Acumen Pharmaceuticals. The company has developed a therapeutic monoclonal antibody in clinical trials that targets the subtype of beta-amyloid oligomers described in this paper.

The NU-9 compound was designed by Richard Silverman, co-author of the study, a professor in Weinberg College’s Department of Chemistry and founder of Akava Therapeutics, the company developing NU-9, now called AKV9.

NU-9 was originally conceived about 15 years ago as part of an effort to develop a “small molecule” compound to stop the accumulation of toxic protein aggregates in neurodegenerative diseases. By 2021, NU-9 had shown benefits in animal models of amyotrophic lateral sclerosis (ALS) by eliminating the toxic proteins SOD1 and TDP-43 and restoring the health of upper motor neurons.

In 2024, the US Food and Drug Administration (FDA) allowed the start of human clinical trials for ALS. In earlier research this year, researchers reported that NU-9 could also effectively treat Alzheimer’s disease after it was seen to eliminate toxic amyloid-beta oligomers in lab-grown brain cells in the hippocampus – a region important for learning and memory.

The authors show that, both in ALS and in Alzheimer’s disease, cells are affected by the accumulation of toxic proteins and that the normal mechanisms for their elimination deteriorate in neurodegenerative diseases; in this context, NU-9 could restore this cellular protection pathway.

To assess whether the drug can stop damage early in Alzheimer’s disease, the team focused on the earliest, pre-symptomatic stage.

In the new study, researchers administered NU-9 orally daily for 60 days to a pre-symptomatic mouse model. The results showed an important decrease in the state in which astrocytes, support cells in the brain, become “reactive” and are associated with an inflammatory response that usually occurs long before the symptoms of the disease are visible.

Also, the number of toxic beta-amyloid oligomers bound to astrocytes (the “star-shaped” brain cells that protect neurons and help regulate inflammation) decreased sharply.

The researchers also observed a major decrease in an abnormal form of the TDP-43 protein, described as a hallmark of neurodegenerative diseases and associated with cognitive impairment. According to the team, the improvements were seen in several brain regions, suggesting an anti-inflammatory effect throughout the brain.

Analyzing how NU-9 acted in pre-symptomatic mice, the researchers described identifying an unexpected “culprit.” Although beta-amyloid oligomers have long been considered more harmful than the beta-amyloid fibrils that later form plaques in Alzheimer’s, this research highlights that not all oligomers are equally harmful.

The Northwestern team identified a subtype that seems particularly problematic. The subtype is called ACU193+, being detected by the ACU193 antibody.

The researchers reported that this occurs early inside the “stressed” neurons, and then the oligomers appear to move to the surface of nearby reactive astrocytes. When ACU193+ oligomers attach to astrocytes, the team suggests, they could help set off an inflammatory chain reaction that spreads throughout the brain long before memory loss begins.

In this study, NU-9 targeted and strongly reduced the ACU193+ subtype, which the researchers say could make the drug particularly useful in the earliest stages of Alzheimer’s disease, when intervention is most effective.

By targeting this subtype of oligomers, NU-9 could help prevent astrocyte activation. The authors note that astrocytes are the brain’s “first responders,” but when they go into a reactive state, they can become harmful; In this state, they can damage synapses, release inflammatory molecules and accelerate neurodegeneration. The study states that preventing this activation could represent one of the most powerful ways to slow the progression of Alzheimer’s disease.

The authors compare the strategy with the idea of ​​early intervention used in other fields of medicine. They cite the example of cholesterol: the presence of a biomarker that signals Alzheimer’s disease could justify, in this logic, the initiation of treatment with NU-9 before symptoms appear.

The authors also note that there are also several early diagnostic blood tests for Alzheimer’s disease under development, the goal being to combine an early diagnosis with a drug that could stop the disease.

Next, the team is testing NU-9 in additional models of Alzheimer’s disease, including an animal model of late-onset disease designed to better approximate typical aging in humans.

The researchers plan to follow the animals over a longer period to see if symptoms develop in the treated ones and to study how early treatment with NU-9 affects memory and neuronal health over time.