Experimental drug can sharply reduce amyloid beta’s impact on Alzheimer’s

Early in Alzheimer’s disease, your brain can begin to change long before anyone notices a lost name or missed appointment. Toxic proteins quietly collect inside cells, support cells turn restless, and inflammation smolders in the background. By the time memory problems show up, much of this damage is already in motion.

A new study from Northwestern University suggests that this early window may be your best chance to fight back. The team has uncovered a previously hidden, highly toxic form of amyloid beta and shown that an experimental drug, called NU-9, can sharply reduce its impact in a mouse model of Alzheimer’s disease.

Alzheimer’s does not start when you first feel confused. It begins many years earlier as small clusters of amyloid beta, called oligomers, build up inside neurons and support cells. These clusters are thought to be more damaging than the larger plaques that appear later.

“Alzheimer’s disease begins decades before its symptoms appear, with early events like toxic amyloid beta oligomers accumulating inside neurons and glial cells becoming reactive long before memory loss is apparent,” said Daniel Kranz, the study’s first author.

That slow, hidden start helps explain why so many clinical trials have failed. Most drugs are tested after symptoms appear, when the underlying damage is already far along. In this new work, the Northwestern team did something different. They treated mice before symptoms, trying to mimic a future in which people at high risk could receive therapy early.

Scientists have known for years that amyloid beta oligomers are bad for brain cells. But not all oligomers are the same. In this study, the researchers identified a particularly harmful subtype that seems to spark some of the earliest changes.

“We identified a distinct amyloid beta oligomer subtype that appears inside neurons and on nearby reactive astrocytes very early in the disease,” Kranz said. “It potentially acts as an instigator of early Alzheimer’s pathology.”

This subtype, called ACU193+ because it is recognized by an antibody named ACU193, first shows up inside stressed neurons. Then it appears to move to the surfaces of nearby astrocytes, the star-shaped cells that support neurons and help control inflammation. Once ACU193+ oligomers latch onto astrocytes, they seem to push these cells into a reactive, pro-inflammatory state.

That shift matters for you because reactive astrocytes can turn from protectors into aggressors. They release inflammatory molecules, damage synapses, and help drive the spread of degeneration across the brain.

NU-9 did not start as an Alzheimer’s drug. About 15 years ago, Northwestern chemist Richard Silverman, who previously invented pregabalin (Lyrica), set out to design a compound that could help cells clear toxic protein aggregates in neurodegenerative diseases.

By 2021, NU-9 had shown strong effects in animal models of ALS, clearing harmful SOD1 and TDP-43 proteins and restoring the health of upper motor neurons. In 2024, it received FDA clearance to begin human clinical trials for ALS.

“In both ALS and Alzheimer’s disease, cells suffer from toxic protein buildup,” said senior author William Klein, a professor of neurobiology at Northwestern. “Cells have a mechanism to get rid of these proteins, but it gets damaged in degenerative diseases like ALS and Alzheimer’s. NU-9 is rescuing the pathway that saves the cell.”

Earlier work from the same group showed that NU-9 could clear toxic amyloid beta oligomers in lab-grown hippocampal neurons, a brain region that supports learning and memory. The new study asks a deeper question that matters directly for future patients: what happens if you give NU-9 before Alzheimer’s really takes off?

To test that question, the team used a mouse model of early-onset Alzheimer’s disease. These animals develop amyloid buildup and brain changes long before they would show clear memory problems.

Researchers gave the mice a daily oral dose of NU-9 for 60 days during this pre-symptomatic period. Then they looked across the brain for early signs of inflammation and protein stress. The results were striking.

NU-9 sharply reduced early reactive astrogliosis, the inflammatory response in astrocytes that usually ramps up long before memory loss appears. The number of toxic amyloid beta oligomers bound to astrocytes dropped as well. An abnormal form of the protein TDP-43, often linked to cognitive decline and other neurodegenerative diseases, also fell dramatically.

“These results are stunning,” Klein told The Brighter Side of News. “NU-9 had an outstanding effect on reactive astrogliosis, which is the essence of neuroinflammation and linked to the early stage of the disease,” he continued.

Importantly for you, these improvements were not confined to a single brain area. NU-9 seemed to have a brain-wide calming effect on astrocytes, cutting back inflammation in multiple regions that are vulnerable in Alzheimer’s.

The same toxic ACU193+ oligomer subtype that NU-9 reduced is also the target of a monoclonal antibody developed by Acumen Pharmaceuticals, a company co-founded by Klein. That antibody is already in clinical trials.

On one side, the ACU193 antibody aims to bind and neutralize this harmful oligomer subtype directly. On the other, NU-9 seeks to restore the cell’s own protein-clearing machinery and stop astrocytes from entering a destructive reactive state.

“The promise of better early diagnostics, combined with a drug that could stop the disease in its tracks, is the goal,” Klein said.

Silverman sees a parallel with heart disease prevention that may resonate with you. “Most people are used to monitoring their cholesterol levels,” he said. “If you have high cholesterol, it doesn’t mean that you will have a heart attack soon. But it’s time to take drugs to lower your cholesterol levels to prevent that heart attack from happening down the road. NU-9 could play a similar role. If someone has a biomarker signaling Alzheimer’s disease, then they could start taking NU-9 before symptoms appear.”

Right now, NU-9 has shown its impact only in animals, and mainly in a model of early-onset disease. The Northwestern team is already testing the compound in additional Alzheimer’s models, including one that better reflects late-onset disease, which is the most common form in people.

They also plan to follow treated animals longer to see whether memory problems still develop and how neuron health changes over time. For you and your family, the most important questions remain: can NU-9 safely reach human brains, and can it delay or prevent memory loss when started early?

The study, “Identification of a glia-associated amyloid beta oligomer subtype and the rescue from reactive astrogliosis by inhibitor NU-9,” was supported by the National Institutes of Health (grant AG061708) and appears in Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association.

How will this work shape the future for people at risk of Alzheimer’s disease? First, it strengthens the case for much earlier diagnosis. If blood tests or imaging can flag toxic amyloid activity or ACU193+ oligomers before symptoms, you might one day have the option to start treatment in a safer window.

Second, the study suggests a new treatment strategy that focuses on calming the brain rather than only clearing plaques. By lowering toxic oligomer subtypes and keeping astrocytes from becoming destructive, drugs like NU-9 could lower inflammation across the brain and slow the chain of events that kills neurons.

Third, the combination of a targeted antibody such as ACU193 with a small molecule like NU-9 may offer a two-step approach: neutralize a key toxic species and restore the cell’s natural cleanup system. That kind of layered therapy could become a model for other neurodegenerative diseases where protein buildup plays a central role.

Finally, this research offers hope that Alzheimer’s does not have to be tackled only at its late, devastating stages. For you, your parents, or your children, the long-term vision is clear: better early tests, followed by preventive treatments that keep toxic proteins in check and preserve healthy brain function for years longer.

Research findings are available online in the journal Alzheimer’s & Dementia.

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