Alzheimer’s disease is a complex neurodegenerative disorder that develops over several decades before clear clinical signs become visible. For many years, both basic and clinical research focused mainly on neuronal integrity and on the amyloid-beta hypothesis, which proposed that the disease could be treated by reducing plaque accumulation in the brain.

This line of research led to the approval of Leqembi (lecanemab), developed by Eisai and Biogen, and Kisunla (donanemab), developed by Eli Lilly. Although these therapies are considered disease-modifying agents, their clinical benefit remains limited and are by no means an acceptable therapeutic solution. Both drugs carry a black box and are associated with a side effect known as amyloid related imaging abnormalities (ARIA) which can cause bleeding in the brain and are contraindicated in patients with one or no copies of the APOE4 gene.

For decades, the importance of glial cells, astrocytes, and the blood-brain barrier vessels clearing waste products from the brain, received far less attention. Encouragingly, these mechanisms are now attracting more interest and more resources. In an article entitled “Moving beyond the amyloid hypothesis”, published in the February 2025 issue of MedNous, we outlined several of these emerging concepts.

Two recent findings of particular interest

The two studies below illustrate how Alzheimer’s research is expanding beyond amyloid removal toward new biological mechanisms and therapeutic strategies.

1. Targeting neuroinflammation through cPLA2 inhibition

In a paper published in npj Drug Discovery, published on January 7, 2026, Anastasiia V. Sadybekov and colleagues at the University of Southern California, Los Angeles (USA), describe a new family of inhibitors designed to reduce neuroinflammation by targeting the calcium-dependent phospholipase A₂ (cPLA₂) an enzyme acting as a critical mediator of inflammatory lipid signaling pathways. To identify promising candidates, the team used V-SYNTHES2, a large-scale virtual screening platform, to explore a chemical space of 36 billion potentially synthesizable compounds. After several rounds of selection, synthesis, and optimization, they identified BRI-50460, a highly potent and selective molecule capable of inhibiting cPLA2 at nanomolar concentrations in cellular assays.

The study also shows that BRI-50460 exhibits adequate characteristics important for a neurological therapeutic : it reaches the central nervous system in animal models, it modulates neuroinflammatory pathways and helps restore cerebral lipid balance in astrocytes and neurons derived from human stem cells, it reduces toxic effects associated with beta-amyloid oligomers, including cPLA2 activation, tau hyperphosphorylation, and synaptic loss.

Taken together, these findings suggest a novel promising therapeutic avenue: acting downstream of brain inflammation to limit certain processes associated with Alzheimer’s disease.

2. Preventing GRK2 aggregation to protect neuronal energy metabolism

In an article published in Cell Reports Medicine (Vol. 7, Issue 4, April 21, 2026), Ursula Quitterer and colleagues at ETH Zurich (Switzerland) describe a new therapeutic approach for Alzheimer’s disease centered on G-protein-coupled receptor kinase 2 (GRK2), an enzyme that normally helps cells regulate their response to stress.

In the brains of patients with dementia, as well as in mouse models of Alzheimer’s disease, the researchers identified an inactive, aggregated form of GRK2. Their findings suggest that this aggregation may drive a self-reinforcing cycle: GRK2 aggregates impair mitochondrial function, increasing cellular stress, which in turn promotes beta-amyloid production and further worsens GRK2 aggregation.

To interrupt this mechanism, the team tested several experimental molecules. One candidate, CPD-10, showed particularly encouraging results in cell-based experiments and in mice. The compound appears to : prevent GRK2 aggregation, improve mitochondrial function, reduce beta-amyloid deposition and protect neurons from degeneration.

By targeting a pathway linked to cellular stress and neuronal energy metabolism, CPD-10 could eventually complement existing therapeutic strategies and help slow disease progression.

Conclusion

None of the compounds discussed above has yet been tested in humans as a treatment for Alzheimer’s disease. These new studies strongly suggest that major academic institutions such as ETH Zurich and the University of Southern California are devoting substantial effort and resources to research on neuroinflammation and on therapeutic pathways that go beyond amyloid removal alone.

^{This document has been prepared by Jean-Claude Muller and is provided for information purposes only. The information contained herein has been obtained from sources believed to be reliable but is not warranted to be accurate or complete. The views presented are those of the author at the time of writing and are subject to change. Jean-Claude Muller has no obligation to update these opinions or the information presented.}