Brain organoids could guide treatment of Alzheimer's disease

Brain organoids, and the tiny particles they secrete, may help to stage early Alzheimer's disease and evaluate drug response.

Brain organoids are three-dimensional brain tissues derived from stem cells that mimic aspects of brain function and are sometimes referred to as 'brains in a dish' (see BioNews 1300, 1245, 1223 and 1177). These organoids also secrete extracellular vesicles, small particles that contain cellular information. Now, researchers have generated patient-derived organoid models and analysed protein profiles from both the organoids and their extracellular vesicles. They aimed to better understand Alzheimer's disease mechanisms and explore sources of variation in individual drug responses.

'Our study suggests that large-scale, patient-derived brain organoids and the vesicles they secrete can help us stage Alzheimer's disease, investigate the mechanisms that drive it and assess how patient subgroups may respond to different treatments,' said Dr Vasiliki Machairaki, associate professor of genetic medicine at Johns Hopkins University in Baltimore, Maryland, who led the study published in Alzheimer's & Dementia.

The researchers generated organoids derived from stem cells collected from blood samples of 30 people, including both Alzheimer's patients and cognitively normal controls. They showed that organoids and secreted extracellular vesicles can reflect molecular-level changes associated with Alzheimer's disease. The organoids revealed changes in immune activity, brain development pathways and communication between nerve cells.

The organoids were also used to assess responses to selective serotonin reuptake inhibitors (SSRIs) – a common class of medication used to manage neuropsychiatric symptoms associated with Alzheimer's disease – helping to explain why they may be effective in some patients but not others.

Extracellular vesicle profiles showed distinct molecular responses to medication, which may help predict individual differences in treatment response in future applications. The extracellular vesicles highlighted changes in neuronal communication, memory-related pathways and other key brain functions.

'We used these organoids to model how some patients' tissue may respond to a commonly prescribed SSRI,' said Dr Machairaki. 'On a large-scale level, our model may eventually be used to identify subgroups of patients, based on underlying molecular mechanisms, who are more likely to respond to certain drugs and thus help us to create precise, targeted treatments in the long run.'

For future work, the team plans to incorporate immune cells and vascular-like networks into the model to improve its biological accuracy and better mimic the structure of the human brain, as well as explore the use of extracellular vesicles for diagnosing and staging subtypes of Alzheimer's disease.

Overall, the study suggests that brain organoids and their secreted extracellular vesicles may serve as useful experimental models for understanding Alzheimer's disease heterogeneity and could, in the future, support more personalised approaches to treatment selection.