Researchers at UTHealth Houston have used single-cell analysis to identify gene disruptions in three brain regions of patients with sporadic early onset Alzheimer's disease. The study, published in Science Advances, addresses a form of Alzheimer's that is both rare and aggressive, affecting individuals under the age of 65.
Sporadic early onset Alzheimer's makes up about 90% of cases among younger patients who do not carry known mutations in the APP, PSEN1, or PSEN2 genes. This population has been largely understudied.
"We focused this study on those with sporadic early onset Alzheimer's disease because there is so much we don't know about it," said Zhongming Zhao, PhD, MS, professor and Chair for Precision Health at McWilliams School of Biomedical Informatics at UTHealth Houston. "Previous studies have typically focused on cells in only one region of the brain from late-onset Alzheimer's disease; we are using a new single-cell technology to map genes in three regions of the brain. And for the very first time, we have a very detailed view of those molecular signals and the gene regulations in the specific brain regions in the specific cell type." Zhao also serves as founding director of both the UTHealth Houston Center for Precision Health and Cancer Genomics Center.
The research team employed advanced single-nucleus multiomics techniques to examine over 76,000 nuclei from three key brain areas: prefrontal cortex, entorhinal cortex, and hippocampus. This approach allowed them to investigate how genes are regulated and expressed within specific cell types.
Their findings show that genes within the entorhinal cortex and hippocampus exhibit significant disruptions consistent with their roles in Alzheimer’s progression. Researchers identified two critical gene regulators: RFX4 in astrocytes (support cells) and IKZF1 in microglia (immune cells). These regulators influence communication between brain cells and immune responses. The study found changes in pathways related to neuroinflammation and neuronal signaling when Alzheimer’s-related pathogens were present. It also explored how glial cells support neurons and how astrocytes may inadvertently damage healthy brain tissue while responding to amyloid plaques.
While some patterns matched those seen in late-onset Alzheimer’s disease, researchers noted unique features associated with sporadic early onset cases—including similarities with conditions such as schizophrenia and bipolar disorder. The results point toward potential therapeutic targets by aiming to restore normal gene regulation and improve intercellular communication.
"Alzheimer's disease is the worst disease there is in that it robs a person of themselves and takes them from their loved ones, a few brain cells at a time," said Paul Schulz, MD, professor of neurology at McGovern Medical School at UTHealth Houston. "This study truly gives us insights into how brain cells, glia, and microglia interact in someone to produce Alzheimer's disease, which we can then use to focus our next studies and then use that knowledge to test rationally designed treatments."
Additional contributors included researchers from various departments within UTHealth Houston as well as Baylor College of Medicine.
