Patient-Derived Neurons Developed to Better Model Late-Onset Alzheimer’s

Researchers at Washington University School of Medicine in St. Louis have developed a method to study aged neurons in the lab, advancing the understanding of Alzheimer's disease. By transforming skin cells from patients with late-onset Alzheimer's into neurons, the scientists have, for the first time, accurately reproduced key dementia features such as amyloid beta buildup, tau protein deposits, and neuronal cell death in lab-derived neurons.

This innovative approach allows researchers to study Alzheimer's without the need for brain biopsies, capturing the effects of aging on the disease. The study, published in Science, highlights the role of retrotransposable elements—genomic factors that change activity with age—in the development of late-onset Alzheimer's, suggesting new treatment strategies targeting these elements.

To date, Alzheimer's research has relied on animal models with early-onset genetic mutations, which do not fully represent the late-onset form of the disease. Yoo's team used cellular reprogramming to transform human skin cells into neurons, retaining the age-related characteristics of the patients' cells. These neurons formed spheroids, mimicking the brain's 3D environment, and exhibited disease hallmarks such as amyloid beta deposits and tau tangles.

The study also demonstrated that early intervention with drugs targeting amyloid beta formation significantly reduced deposits, while later treatments had limited effects. Additionally, inhibiting retrotransposable elements with the drug lamivudine reduced amyloid beta and tau tangles and decreased neuronal death in late-onset Alzheimer's spheroids, but not in early-onset cases.

“In these patients, our new model system has identified a role for retrotransposable elements associated with the disease process,” said Andrew Yoo, senior author of the paper. “We were pleased to see that we could reduce the damage with a drug treatment that suppresses these elements. We look forward to using this model system as we work toward new personalized therapeutic interventions for late-onset Alzheimer’s disease.”