An experimental drug developed at Northwestern University has demonstrated further promise as an early intervention for Alzheimer’s disease. In a new study, Northwestern University scientists identified a previously unknown highly toxic sub-species of amyloid beta oligomers that appear to drive several of the brain’s earliest changes.
The experimental drug, a small-molecule compound called NU-9, decreased this toxic amyloid beta oligomer subtype 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 could prevent, or significantly delay, the toxic events that destroy neurons.
Conceived about 15 years ago, NU-9 emerged as part of a 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, researchers demonstrated that NU-9 also could effectively treat Alzheimer’s disease. In a previous study, NU-9 showed it could clear toxic amyloid beta oligomers in lab-grown brain cells from the hippocampus.
In this new study, researchers from Northwestern University administered NU-9 to a pre-symptomatic mouse model of Alzheimer’s disease every day for 60 days. It worked well—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—decreased.
The researchers said improvements spanned multiple regions of the brain, indicating that NU-9 has a brain-wide anti-inflammatory effect.
During their research, the team made an additional unexpected discovery. 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 a problematic subtype called ACU193+ that shows up early inside of stressed neurons. Then, these oligomers appear to migrate to the surfaces of nearby astrocytes. When ACU193+ oligomers latch onto astrocytes, they can spark a cascade of inflammation that spreads throughout the brain—long before memory loss begins.
The collective findings point to a potential new strategy for targeting the disease in its earliest stages—before cognitive decline and other debilitating symptoms take hold.
“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.
Data from Northwestern University