Experimental drug targets early toxic amyloid to slow Alzheimer’s disease

An experimental drug developed at Northwestern University has demonstrated further promise as an early intervention for Alzheimer's disease.

In a new study, Northwestern scientists identified a previously unknown highly toxic sub-species of amyloid beta oligomers - toxic clusters of peptides - that appear to drive several of the brain's earliest changes, including neuronal dysfunction, inflammation and activation of immune cells.

The experimental drug, a small-molecule compound called NU-9, decreased this toxic amyloid beta oligomersubtype and dramatically reduced the damage it causes in a mouse model of Alzheimer's disease. By addressing these changes at the onset of Alzheimer's disease, the researchers are hopeful NU-9 potentially could prevent, or significantly delay, the cascade of toxic events that ultimately destroy neurons.

The findings point to a potential new strategy for targeting the disease in its earliest stages - before cognitive decline and other debilitating symptoms take hold.

The study will be published on Dec. 18 in Alzheimer's and Dementia: The Journal of the Alzheimer's Association.

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. By the time symptoms emerge, the underlying pathology is already advanced. This is likely a major reason many clinical trials have failed. They start far too late. In our study, we administered NU-9 before symptom onset, modeling this early, pre-symptomatic window." Daniel Kranz, study's first author, Northwestern University

Kranz is a recent Ph.D. graduate from the Interdisciplinary Biological Sciences (IBiS) program at Northwestern's Weinberg College of Arts and Sciences, where he is advised by corresponding author William Klein. An expert on Alzheimer's disease, Klein is a professor of neurobiology at Weinberg and a cofounder of Acumen Pharmaceuticals, which has developed a therapeutic monoclonal antibody currently in clinical trials that targets the subtype of amyloid beta oligomers identified in the study. Richard Silverman, a key co-author of the study, invented NU-9. Silverman, who previously invented pregabalin (Lyrica) to treat fibromyalgia, nerve pain and epilepsy, is the Patrick G. Ryan/Aon Professor in Weinberg's Department of Chemistry and founder of Akava Therapeutics, a startup company commercializing NU-9 (now called AKV9).

The promise of NU-9

Conceived about 15 years ago, NU-9 emerged as part of Silverman's multi-year effort to discover a small molecule compound that could prevent toxic protein aggregate buildup in neurodegenerative diseases. By 2021, NU-9 demonstrated efficacy in animal models of amyotrophic lateral sclerosis (ALS), clearing toxic SOD1 and TDP-43 proteins and restoring health to upper motor neurons. In 2024, it received clearance from the U.S. Food and Drug Administration to begin human clinical trials for ALS.

Earlier this year, Silverman, Klein and Kranz demonstrated that NU-9 also could effectively treat Alzheimer's disease. In the previous study, NU-9 showed it could clear toxic amyloid beta oligomers in lab-grown brain cells from the hippocampus, a region critical for learning and memory.

"In both ALS and Alzheimer's disease, cells suffer from toxic protein buildup," Klein said. "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."

Early intervention

To further investigate the drug's potential in treating Alzheimer's disease, the team wanted to evaluate its effectiveness at halting the earliest damage. In the new study, the researchers administered NU-9 to a pre-symptomatic mouse model of Alzheimer's disease. The mice received a daily oral dose for 60 days.

The results were striking. NU-9 significantly reduced early reactive astrogliosis, an inflammatory reaction that typically begins long before symptoms appear. The number of toxic amyloid beta oligomers bound to astrocytes (star-shaped brain cells that protect neurons and control inflammation) also plummeted. And an abnormal form of the protein TDP-43 - a hallmark of neurodegenerative diseases that is linked to cognitive impairments - sharply decreased.

"These results are stunning," Klein said. "NU-9 had an outstanding effect on reactive astrogliosis, which is the essence of neuroinflammation and linked to the early stage of the disease."

The improvements spanned multiple regions of the brain, indicating that NU-9 has a brain-wide anti-inflammatory effect.

A hidden culprit

While investigating the effects of NU-9 on the pre-symptomatic mouse model, the research team found an unexpected culprit. For decades, scientists have considered amyloid beta oligomers as more toxic than the larger amyloid beta fibrils that form plaques, which appear later in Alzheimer's disease. But not all amyloid beta oligomers are the same. The Northwestern scientists discovered one uniquely problematic subtype.

"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."

Called ACU193+ because it is detected by the antibody ACU193, the subtype shows up early inside of stressed neurons, the scientists found. Then, these oligomers appear to migrate to the surfaces of nearby astrocytes. When ACU193+ oligomers latch onto astrocytes, they may spark a cascade of inflammation that spreads throughout the brain, long before memory loss begins.

A potential prophylaxis

NU-9 targeted and dramatically reduced this subtype, suggesting the drug may be especially valuable at Alzheimer's earliest stages, when intervention is most effective. By reducing this subtype, NU-9 potentially could prevent the activation of astrocytes.

Although they serve as the brain's frontline responders, astrocytes become destructive when pushed into a reactive state. This destructive behavior damages synapses, releases inflammatory molecules and accelerates neurodegeneration. Stopping this process might be one of the most powerful ways to slow the progression of Alzheimer's disease.

Kranz and Silverman likened the strategy to early intervention approaches for preventing cancer and heart disease.

"Most people are used to monitoring their cholesterol levels," Silverman 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."

"There are a couple early diagnostic blood tests for Alzheimer's disease in development," Klein added. "The promise of better early diagnostics - combined with a drug that could stop the disease in its tracks - is the goal."

Currently, the team is testing NU-9 in additional models of Alzheimer's disease, including an animal model of late-onset disease that better reflects typical human aging. The researchers also plan to follow animals for a longer period of time to determine whether symptoms develop in treated animals and plan to examine how early intervention with NU-9 affects memory and neuron health over time.

Kranz, D. L., et al. (2025). Identification of a glia‐associated amyloid β oligomer subtype and the rescue from reactive astrogliosis by inhibitor NU‐9. Alzheimer’s & Dementia. doi: 10.1002/alz.70968. https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.70968