Small-Molecule Alzheimer's Therapy Shows Promise in Mice, Trial

A small molecule therapy for Alzheimer's disease that targets the brain's microglia cells protects neurons in a mouse model and is safe in humans, according to new research that includes results from a phase 1 trial involving 115 participants and patients. The therapy stands at the leading edge of a new class of experimental drugs that target microglia through small molecules rather than antibodies, the latter of which have faced various obstacles to translation. Current treatments for Alzheimer's disease can break down the amyloid-beta protein that damages neurons, but they yield only modest clinical benefits. Researchers are searching for other targets and have recently focused on microglia, which are immune cells whose duties include maintaining neural networks and clearing cellular debris. Microglia contain a transmembrane receptor named TREM2, which supports the cells' ability to respond to signs of disease and to break down amyloid-beta. Furthermore, genetic studies have identified some mutations in TREM2 that correlate with a higher risk of late-onset Alzheimer's disease. Here, Borislav Dejanovic and colleagues engineered two small molecules that activate human TREM2, named VG-3927 and VG-3909. The compounds reduced markers of neuronal damage and inflammatory signaling when given to cultured neurons and microglia, and boosted microglia's ability to break down amyloid-beta in a mouse model. The team then tested ascending doses of the small molecules in a phase 1 trial, showing that it was well-tolerated and penetrated the central nervous system. It also reduced levels of a marker of TREM2 in the cerebrospinal fluid in patients with Alzheimer's disease – a promising finding in the nascent field of TREM2-targeted therapies.