Brain Organoids Reveal Why Alzheimer's Patients Respond Differently to Common Antidepressants
Key Insights
Johns Hopkins researchers developed patient-derived hindbrain organoids that capture key molecular features of Alzheimer's disease (search) and reveal individual variation in drug response.
When exposed to the SSRI escitalopram oxalate, some organoids showed strong molecular responses while others showed little change, mirroring real-world clinical variability.
Extracellular vesicles released by organoids contained Alzheimer's-linked proteins including RAB3A (search), NSF (search), and ATCAY (search) at lower levels, suggesting potential as non-invasive biomarkers.
More than 7 million Americans live with Alzheimer's disease (search), and nearly all experience neuropsychiatric symptoms such as anxiety, depression, and agitation. Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed to manage these symptoms, yet two patients with similar diagnoses can respond very differently to the same medication — leaving clinicians with few tools to predict who will benefit.
Now, researchers at Johns Hopkins Medicine have developed miniature brain models grown from patients' own cells that may help explain those differences. The study, published in Alzheimer's & Dementia: The Journal of the Alzheimer's Association, suggests these lab-grown tissues can capture key biological features of Alzheimer's disease (search) and reveal how individual patients might respond to commonly prescribed medications.
"Our study suggests that large-scale, patient-derived brain organoids and the vesicles they secrete can help us stage Alzheimer's disease (search), investigate the mechanisms that drive it and assess how patient subgroups may respond to different treatments," said study leader Vasiliki Machairaki, Ph.D., associate professor of genetic medicine at the Johns Hopkins University School of Medicine.
Building Miniature Brains from Patient Blood
The research team began with blood samples collected from patients enrolled in the NIH-funded Johns Hopkins Alzheimer's Disease (search) Research Center. Those cells were reprogrammed into induced pluripotent stem cells, which can develop into nearly any cell type in the body.
Using stem cells from both Alzheimer's patients and healthy volunteers, the researchers produced hindbrain organoids containing serotonin-producing neurons. The hindbrain plays an important role in regulating functions such as sleep, breathing, and heart rate, while serotonin signaling has long been linked to mood and behavior. The cells organized themselves into pea-sized structures that resembled aspects of the human hindbrain.
According to Machairaki, the study may be among the largest Alzheimer's investigations to use patient-derived brain organoids, involving hundreds of organoids from both patients and healthy individuals.
Molecular Differences Emerge Between Patient Groups
When the researchers compared organoids from Alzheimer's patients with those from healthy individuals, they found clear molecular differences. Proteins involved in cell communication, inflammation, and other disease-related processes were altered in the Alzheimer's-derived tissues.
The team then exposed the organoids to escitalopram oxalate, a widely prescribed antidepressant in the SSRI class. Some organoids responded strongly, showing increases in proteins associated with serotonin signaling and communication between neurons. Others showed little or no measurable change.
That variation closely mirrors what doctors observe in real patients, where responses to the same medication can differ dramatically despite similar diagnoses.
"We used these organoids to model how some patients' tissue may respond to a commonly prescribed SSRI," Machairaki said. "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."
Extracellular Vesicles as Potential Biomarkers
The researchers also examined extracellular vesicles — microscopic particles released by cells that transport proteins and other biological material throughout the body. Because these particles can be detected in bodily fluids such as blood, scientists are increasingly studying them as potential sources of disease biomarkers that could be measured without invasive procedures.
Before and after escitalopram treatment, the team analyzed extracellular vesicles released by both Alzheimer's-derived organoids and healthy controls. The vesicles contained proteins involved in memory, neurotransmitter release, and communication between neurons.
Several proteins linked to Alzheimer's disease (search), including RAB3A (search), NSF (search), and ATCAY (search), appeared at lower levels in organoids derived from patients with the disease. After treatment, some of those proteins increased in certain samples, particularly proteins associated with serotonin signaling and synaptic activity.
As with the organoids themselves, responses varied considerably between samples. Some showed substantial molecular changes, while others showed almost none.
Toward Personalized Alzheimer's Care
The findings suggest that extracellular vesicles could eventually help identify which patients are most likely to benefit from specific therapies, potentially allowing treatments to be matched more closely to the biology of an individual's disease.
The researchers are now working to create more advanced organoids that include immune cells and vessel-like networks that mimic blood vessels. These additions could make the models more representative of the living human brain and improve their value for studying Alzheimer's disease (search).
Looking ahead, Machairaki envisions a future in which extracellular vesicles serve as a type of liquid biopsy, helping doctors diagnose Alzheimer's disease (search), determine its stage, and identify distinct biological subtypes that may require different treatment approaches.
The study was funded by the National Institutes of Health, the Paul G. Allen Frontiers Foundation, and the Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease (search) at The Johns Hopkins University. Scientists contributing to the work included Rachel Boyd, Daiyun Dong, Ram Sagar, Waqar Ahmed, Xenia Androni, Paul Rosenberg, Constantine Lyketsos, and Kenneth Witwer from Johns Hopkins; Anton Iliuk from Tymora Analytical Operations; and Anton Porsteinsson from the University of Rochester School of Medicine and Dentistry.