Innovative brain model provides patient-specific Alzheimer’s insights

A team from Bringham and Women’s Hospital, US, have developed a new brain model that can predict the rate of cognitive decline in individuals with Alzheimer’s disease (AD). The researchers hope their model can be used to predict the efficiency of drugs in specific groups of AD patients.

The team generated induced pluripotent stem cell (iPSC) lines from over 50 different individuals for whom longitudinal clinical data, quantitative neuropathology data and rich genetic and molecular profiling of brain tissue was also available. They subsequently turned these stem cells into brain cells and then analysed molecular pathways active in these living neurons in a dish.

The researchers measured amyloid beta-protein (Aβ) and tau protein generated by the stem cell-derived neurons and found that specific Aβ and tau species were associated with the levels of plaque and tangle deposition in the brain and the trajectory of cognitive decline.

“If you look across cell culture samples from 50 people, you can predict from the Aβ and tau profiles some features of the cognitive status of that person. Their rate of cognitive decline and whether they developed AD, which is absolutely remarkable,” said researcher Tracy Young-Pearse. “This is a resource for the whole community, for scientists around the world to use… We already have around 50 labs, all around the world, starting to use these cells in their studies.”

The team is also exploring if the stem cell-derived neurons can be used to predict whether drugs such as aducanumab will be more effective in specific groups of AD patients.

“The new Alzheimer’s drug is an antibody that recognises Aβ and clears it from the brain. Our work shows that different genetic backgrounds of human neurons produce different profiles of Aβ,” Young-Pearse stated. “What our system provides is a platform to test who might be responsive to different AD therapeutics, for example, anti-Aβ and anti-tau immunotherapeutics. This will be important because neurons from different individuals produce different profiles of Aβ and tau and different antibody cocktails may be more effective against one profile over another.”

The researchers hope to convey to the public that AD is usually not caused by a single genetic mutation but can have different sets of genes contributing to risk across different people. This means that the primary causes of AD can be varied and treatments may need to be tailored to the underlying causes of disease.

“There is a perception that this disease is one uniform disease that shows up and progresses the same way for everyone,” Young-Pearse explained. “It is important to understand that AD is actually quite heterogeneous in its underlying causes, ages of onset and disease course. This is the first time we have a system in place to study living human brain cells from many people to understand better why some develop AD in a very specific way and others are resistant to the disease.”

The study was published in Neuron.