New Alzheimer's Drug Reprograms The Brain, Not Just Eliminates Plaques

The study presents the development of a new substance, FLAV-27, designed to act on epigenetic mechanisms involved in Alzheimer's disease. Tests in cells, worms, and mice showed that the compound can reduce brain damage, improve memory, and decrease inflammation. Furthermore, biological markers were identified in humans that reinforce the relevance of these findings. The results indicate that FLAV-27 is a promising candidate for future therapies capable of modifying the course of the disease.

Alzheimer's disease is one of the most challenging conditions in modern medicine. It is a disease that progressively affects the brain, leading to memory loss, difficulty in reasoning, and changes in behavior.

With the aging of the world's population, the number of people affected is growing rapidly, making this condition a major global health problem. Despite decades of intense research, there are still no treatments capable of halting or reversing the progression of the disease, making the search for new therapeutic approaches urgent.

One of the reasons why Alzheimer's is so difficult to treat is its complexity. The disease does not have a single cause, but rather a combination of factors involving inflammation in the brain, accumulation of abnormal proteins, and malfunctions in neurons.

In addition, there is a natural barrier in the body called the blood-brain barrier, which protects the brain but also hinders the entry of medications, limiting the effectiveness of many treatments. This set of challenges has led scientists to explore new ways to understand and treat the disease.

In recent years, researchers' attention has turned to a field called epigenetics, which studies how genes can be "switched on" or "switched off" without altering the DNA itself. Unlike genetic mutations, which are permanent, these epigenetic alterations are reversible, making them a promising target for drug development.

Within this context, certain proteins that regulate these modifications, such as methyltransferases, have been investigated for their role in brain function and memory.

Among these proteins, one called G9a has stood out. It acts by controlling the activity of genes important for neurons, especially those involved in communication between brain cells and in the formation of memories.

When this protein functions abnormally, it can contribute to harmful processes such as brain inflammation, cellular stress, and neuronal damage, all associated with Alzheimer's disease. Therefore, blocking the action of this protein has been considered a promising strategy for treating the disease.

However, developing drugs capable of inhibiting this protein has not been simple. Previously created substances presented significant problems, such as low precision, toxic effects, and difficulty reaching the brain.

To overcome these limitations, researchers developed a new molecule called FLAV-27. This compound was designed to act more specifically and efficiently, and to be able to cross the protective blood-brain barrier, which is essential for any treatment aimed at neurological diseases.

Researchers from the Faculty of Pharmacy and Food Sciences at the University of Barcelona involved in this study. Credit: University of Barcelona.

To assess whether FLAV-27 could actually be useful, the scientists conducted a series of detailed experiments. They began by testing the substance on cells grown in the laboratory, including neurons and cells involved in brain inflammation.

Then, they moved on to studies in different living organisms, such as a small worm widely used in biological research and mouse models that develop characteristics similar to human Alzheimer's. This multi-level approach allows them to observe both molecular effects and changes in behavior and memory.

The results were quite promising. FLAV-27 managed to reduce harmful changes associated with Alzheimer's, such as the accumulation of toxic proteins in the brain and inflammation. In animals, the treatment led to improvements in memory, learning ability, and even social behavior.

The image shows a comparison between neurons from mice with Alzheimer's disease-like characteristics that did not receive treatment and those treated with the substance FLAV-27. In the upper images, it is possible to observe that the neurons in the treated group have more branching and connections, indicating a healthier and more active structure. In the lower images, which enlarge parts of these cells, it is noted that the treated neurons have a higher density of small structures called dendritic spines, which are essential for communication between brain cells. Together, these findings suggest that FLAV-27 helps preserve or restore the ability of neurons to connect and transmit information, which is directly related to memory and learning.

In addition, the compound helped restore the activity of genes important for the protection of neurons. In analyses of human samples, researchers also identified biological markers related to these changes, suggesting that the effects observed in the experiments may have clinical relevance.

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First-in-class SAM-competitive G9a inhibitor FLAV-27 as a disease-modifying therapy for Alzheimer disease

Aina Bellver-Sanchis, David Valle-Garcia, Carla Barbaraci, Fernando Romero-Becerra, Rohit Kumar Singh, Júlia Jarne-Ferrer, Foteini Vasilopoulou, Alba Irisarri, Carmen Martínez-Fernández, Juan A. Fafián-Labora, María C. Arufe, Carolin Wüst, Aida Castellanos, David Soto, Núria Casals, Rut Fadó, Jennifer M. Pocock, Gemma Navarro, Cristina Val, José Brea, M. Isabel Loza, Albert Lleó, Juan Fortea, Daniel Alcolea, Anna Perez-Bosque, Lluïsa Miró, Belén Pérez, Sajid Rashid, Muhammad Ali, Manahil Saqib, Marcel lí Carbó, Ana Guerrero, Santiago Vázquez, Bhanwar Singh Choudhary, Shaodong Dai, Carmen Escolano, Rafael Franco, Mercè Pallàs, and Christian Griñán-Ferré

Molecular Therapy. 23 December 2025; 34, 2372-2407

DOI: 10.1016/j.ymthe.2025.12.038

Abstract:

Alzheimer's disease (AD) is characterized by a progressive cognitive decline involving a multifactorial pathophysiology, including epigenetic dysregulation. Here, we report the discovery and preclinical validation of FLAV-27, a first-in-class, S-adenosyl-l-methionine (SAM)-competitive, brain-penetrant, and selective inhibitor of the histone methyltransferase G9a. Unlike prior G9a/GLP inhibitors, FLAV-27 exhibits subnanomolar potency, over 30-fold selectivity, and robust central nervous system bioavailability. Structural studies confirm a unique SAM-binding mode that confers superior specificity and avoids off-target effects. FLAV-27 reduces amyloid beta (Aβ) and p-tau aggregation and restores neuritic complexity in vitro. In Caenorhabditis elegans, it improves mobility, lifespan, and mitochondrial respiration. In mouse models of both late-onset AD (SAMP8) and early-onset AD (5xFAD), FLAV-27 rescues memory performance, social behavior, and synaptic structure. Multi-omics analyses reveal a global reprogramming of H3K9me2/H3K18me-mediated repression, reduced ferroptosis vulnerabilities, and normalization of AD-linked biomarkers, including SMOC1, H3K9me2, and p-Tau181, in the plasma and brain. Our findings position FLAV-27 as a promising epigenetic therapeutic with disease-modifying potential and translational biomarker alignment in AD.