Eli Lily scientists report that ceperognastat, a putative treatment for Alzheimer’s Disease, did not provide any meaningful benefits in phase 2 clinical trials. The news isn’t all bad, however, the drug may have failed in clinical trials, but it still tells us something useful about how the disease works.
Alzheimer’s specialists tested the drug, also known as LY3372689, against a placebo in a randomized controlled trial. They aimed to discover whether it could slow cognitive decline in patients with mild cognitive impairment, as measured on the mini mental compared to a sugar pill.
Double Blind Randomized Controlled Trial
Three hundred and twenty-seven Alzheimers patients aged between 60 and 85 scoring 22–30 on the MMSE, and or a Clinical Dementia Rating Scale (CDR) global score of 0.5 or 1 and evidence of elevated Tau, according to blood tests and PET imaging, tried the experimental treatment at 72 medical centres across Australia, Canada, Japan, Poland, and the US between September 2021 to July 2025.
The researchers observed no differences in the rate of cognitive decline between the placebo group and the ceperognastat group after two years at doses of 0.75 mg or 3 mg. Not only did the drug fail to help, it may have accelerated deterioration in participants taking the higher dose.
Ceperognastat, Tau and Alzheimer’s Disease
Doctors had hoped that the small molecule LY3372689 or ceperognastat could slow the onset of cognitive decline by targeting enzymes that modify a structural protein found in neurons-Tau. Some scientists believe that rogue Tau is responsible for damage to neurons that eventually causes Alzheimers. Others speculate that its primary value lies in its role as a biomarker. Observing aggregates of this protein is a sign that our brain is already accumulating damage.
While this trial showed that ceperognastat might not be a viable treatment for Alzheimers, the trial was still valuable. Although the drug did not help slow cognitive decline, PET scans did demonstrate that patients who used the drug accrued fewer Tau aggregates in the lateral temporal lobes during the course of the study. They also lost less brain volume- particularly in the bilateral hippocampus, and had lower levels of phosphorylated Tau proteins in their blood.
Negative Result, Useful Information
This is relevant and useful information because it will help researchers to narrow down the mechanisms that cause Alzheimer’s disease. If it is confirmed that preventing phosphorylation of Tau or reducing Tau aggregates does not help to protect cognitive function, it tells us that Tau might not be involved in causing the disease. This will guide neuroscientists focus to more likely candidates rather than spending a lot of time on Tau.
This study doesn’t show that Tau is not involved in cognitive decline at all, but it does show that Tau accumulations mediated by the enzyme O-linked N-acetylglucosaminidase are not a priority.
Sources
Fleisher AS, Munsie L, Mancini M, et al. Ceperognastat in Early Symptomatic Alzheimer Disease: A Randomized Clinical Trial. JAMA. Published online July 13, 2026. doi:10.1001/jama.2026.12768
Rabinovici GD, Grill JD. Ceperognastat in Alzheimer Disease: Lessons From a Negative Clinical Trial. JAMA. Published online July 13, 2026. doi:10.1001/jama.2026.12323
