Neuroinflammation: Alzheimer's Emerging Target

Over a century ago, Alois Alzheimer identified the involvement of neuroinflammation in the etiology of the condition that now bears his name. His initial illustrations depicted cells, which are now recognized as microglia, the brain's immune cells. Bruce Lamb, executive director of the Paul and Carole Stark Neurosciences Research Institute and co-founder of Monument Biosciences, a company investigating neuroinflammation-focused Alzheimer's treatments, highlighted Alzheimer's early recognition of the potential role of these cells.

Recent studies have solidified the connection between neuroinflammation and Alzheimer's disease, with microglia emerging as the primary suspects. Lamb explained that there is a clear microglial reaction from the moment amyloid begins to accumulate in the brain, which could be the source of neuronal dysfunction.

In the past fifteen years, there has been a resurgence of interest in the function of microglia in Alzheimer's, partly due to genetic discoveries related to late-onset Alzheimer's disease. Genome-wide association studies and the identification of rare familial mutations have resulted in a list of genes associated with Alzheimer's, most of which are expressed in microglia.

Transcriptomics, proteomics, and metabolomics data from human subjects have corroborated these findings, showing that many of the disturbed networks and pathways, particularly in late-onset Alzheimer's, are part of inflammatory networks.

Various biotech firms are exploring different targets under the hypothesis that neuroinflammation is a contributor to Alzheimer's. Vigil Neuroscience and Alector Therapeutics are investigating the role of TREM2 in microglial dysregulation. TREM2 is expressed on microglia in response to amyloid deposits and is linked to a signaling cascade within the microglia that involves other Alzheimer's-related genes.

Cerevance is focusing on the KCNK13 gene, which is specific to and upregulated in microglia. The company's asset, CVN293, which targets this gene, has shown minimal impact on the peripheral immune system while reducing brain neuroinflammation in preclinical models. Cerevance is currently conducting a Phase I study of this compound, with results expected in 2024.

NeuroTherapia is developing a CB2 receptor agonist, NTRX-07, for Alzheimer's disease, based on findings that microglia upregulate the CB2 receptor and that CB2 agonists can shift microglia from a proinflammatory to an anti-inflammatory state, improving amyloid clearance and neuronal function.

Both Giordano and Thompson concur that a multifaceted approach is necessary to treat Alzheimer's, which is a complex disease. They believe that a combination of treatments will be required, with neuroinflammatory inhibitors being a part of the therapeutic cocktail.

Lamb also mentioned that anti-amyloid antibodies, such as Leqembi, primarily function through microglia, which have FC receptors that bind to antibodies and facilitate the removal of amyloid from the brain. He noted that there is significant interest in combining monoclonal antibodies with drugs that target microglia to improve amyloid removal or prevent side effects associated with these antibodies.

Lamb expressed his belief that immune pathways are at the forefront of discussions for the next breakthrough in Alzheimer's treatment.