Predicting Response to Alzheimer's Disease Treatment with Gene Variant

Predicting which patients respond to investigational therapy in development for Alzheimer’s disease may be possible using a gene variant, according to findings published in Cell Stem Cell.

Researchers from the University of California, San Diego School of Medicine obtained skin cells from 13 human participants in order to analyze in vitro and in vivo models. Seven of the patients had Alzheimer’s disease and 6 were healthy control subjects. The researchers re-engineered the skin cells into stem cells and then guided the cells into becoming neurons. The neurons were cultured and treated with the protective compound called brain derived neutrophic factor (BDNF). Currently, BDNF is being investigated as a potential target therapy for neurological diseases like Alzheimer’s disease. It shows promising levels of neuronal survival.

The genetic risk factor was identified as variants of the SORL1 gene, which codes for a protein that can affect the buildup of beta amyloid peptides. The peptides have been linked to neuronal death and related dementia. In previous studies, variants of the SORL1 gene have demonstrated some protection from Alzheimer’s disease. However, other variants of the disease are linked to nearly a 30% higher likelihood of developing Alzheimer’s disease.

“Our results suggest that certain gene variants allow us to reduce the amount of beta amyloid produced by neurons,” senior author Lawrence Goldstein, PhD, director of UC San Diego Sanford Stem Cell Clinical Center and UC San Diego Stem Cell Program, explained in a press release. “This is potentially significant for slowing the progression of Alzheimer’s disease.”

The researchers found that the neurons that carried the disease prohibitive SORL1 variants responded to the treatment by reducing their baseline rate of beta amyloid peptide production by 20%, on average. The neurons that carried the risk variants of the gene demonstrated no changes in baseline beta amyloid production, the researchers said.

“BDNF is found in everyone’s brain,” said first author Jessica Young, PhD, in the statement. “What we found is that if you add more BDNF to neurons that carry a genetic risk factor for the disease, the neurons don’t respond. Those with the protective genetic profile do. The value of this kind of stem cell study is that it lets us probe the uniquely human aspects of disease and identify how a person’s DNA might determine their drug response, in this case to a potential treatment for Alzheimer’s disease. Future clinical trials on BDNF should consider stratifying patients based on their SORL1 risk factor and likelihood of benefiting from the therapy.”