Single Gene Identified as Culprit in Early-Onset Dementia

Researchers say a mutation in the MAPT gene, which codes for the protein tau, makes it difficult for neurons in the brain to communicate.

Early-onset dementia, unlike Alzheimer’s disease, occurs in younger people. Frontotemporal dementia is estimated to be responsible for approximately one-fifth of all cases of early-onset dementia. Memory loss generally begins to occur when patients are in their early 60s, but for some it begins when they are in their 40s. Currently, there are no effective treatments.

Researchers at Washington University School of Medicine in St. Louis have determined that a single mutation in a specific gene causes an inherited form of frontotemporal dementia in which neurodegeneration occurs because the neurons in the brain can no longer easily communicate with one another.

The gene in question is the microtubule-associated protein tau (MAPT) gene, which is responsible for the production of tau proteins. Tau proteins stabilize the microtubules in neurons. Defective or nonfunctional tau proteins have been associated with diseases of the nervous system, including dementia and Parkinson’s disease.

The approach used by the researchers to identify the gene involved studying both human cells cultured in the lab and cells from individuals suffering with frontotemporal dementia. Skin cells from patients with frontotemporal dementia who were known to have a specific mutation in the MAPT gene were converted into induced pluripotent stem cells. The stem cells were then treated in such a way as to encourage them to grow into neurons containing the MAPT mutation. Using CRISPR gene-editing technology, the mutation was then eliminated in only some of the neurons.

The key differences observed for the cells harboring the mutation were related to cellular communication. Notably, alterations were observed in 61 other genes, including those that code for λ-aminobutyric acid (GABA) receptors on brain neurons, which play important roles in the communication pathways between brain cells. Similar alterations were observed in animal models and the brain tissue of patients with frontotemporal dementia who had died.

The results suggest that not only the MAPT gene but also the other genes downstream from MAPT that are altered may be attractive as drug targets. The researchers also believe that, by studying this rare form of dementia, it may be possible to identify means for treating patients with more common disorders.

David Alvaro, Ph.D.

David is Scientific Editorial Director for That’s Nice and the Pharma’s Almanac content enterprise, responsible for directing and generating industry, scientific and research-based content, including client-owned strategic content. Before joining That’s Nice, David served as a scientific editor for the multidisciplinary scientific journal Annals of the New York Academy of Sciences. He received a B.A. in Biology from New York University and a Ph.D. in Genetics and Development from Columbia University.