Scientists at Northwestern University have identified a toxic subtype of amyloid beta oligomers that triggers early Alzheimer's changes in the brain. Their experimental drug, NU-9, reduced this damage and inflammation in pre-symptomatic mice, suggesting potential for preventing the disease before symptoms appear. The findings highlight a new strategy for early intervention.
Researchers at Northwestern University have pinpointed a previously unknown subtype of amyloid beta oligomers, dubbed ACU193+, as a key driver of Alzheimer's earliest brain changes. This toxic cluster appears inside stressed neurons and on nearby astrocytes early in the disease, potentially sparking widespread inflammation that precedes memory loss by decades.
In a study published on December 18 in Alzheimer's & Dementia: The Journal of the Alzheimer's Association, the team tested NU-9, a small-molecule compound invented by chemist Richard Silverman. Administered orally to pre-symptomatic mice for 60 days, NU-9 dramatically lowered levels of ACU193+ oligomers bound to astrocytes and reduced reactive astrogliosis, an inflammatory response in star-shaped brain cells. It also decreased abnormal TDP-43 protein, linked to cognitive decline, across multiple brain regions.
"These results are stunning," said neurobiologist William Klein, a study co-author and Acumen Pharmaceuticals cofounder. "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 drug, now called AKV9 and commercialized by Silverman's startup Akava Therapeutics, builds on prior work. Conceived 15 years ago, NU-9 cleared toxic proteins in ALS models by 2021 and gained FDA clearance for human ALS trials in 2024. An earlier 2024 study showed it removing amyloid beta oligomers from lab-grown hippocampal cells.
"Alzheimer's disease begins decades before its symptoms appear, with early events like toxic amyloid beta oligomers accumulating inside neurons," noted first author Daniel Kranz, a recent Northwestern Ph.D. graduate. "By the time symptoms emerge, the underlying pathology is already advanced."
The researchers compare NU-9 to cholesterol-lowering drugs for heart disease prevention. "If someone has a biomarker signaling Alzheimer's disease, then they could start taking NU-9 before symptoms appear," Silverman said. Ongoing tests include late-onset disease models and long-term memory assessments. The work was funded by the National Institutes of Health (grant AG061708).
