UTHealth Houston researchers map gene disruptions in sporadic early onset Alzheimer’s disease across key brain regions

A new study led by researchers at UTHealth Houston investigated both gene expression and regulation at single cell levels to reveal disruptions in gene function in three brain regions of patients with sporadic early onset Alzheimer’s disease.

The findings were published in Science Advances.

Only about 5% to 10% of patients with Alzheimer’s disease are younger than 65. Of those patients, 10% have mutations in the APP, PSEN1, and PSEN2 genes, which are associated with Alzheimer’s disease. The other 90% of these cases are classified as sporadic early onset Alzheimer’s, a rare and aggressive form of the disease that begins before age 65. The genetic tie in early onset Alzheimer’s is largely unidentified, representing a significant but understudied population. 

“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.” He is also the founding director of the UTHealth Houston Center for Precision Health and the UTHealth Houston Cancer Genomics Center.

Researchers used advanced single-nucleus multiomics techniques to study brains affected by early onset Alzheimer’s disease. This technique isolates the nucleus of each cell so researchers can study the layers of biological information to build a picture of how genes are regulated and expressed in specific cell types. 

Using this technique, researchers analyzed the three brain regions critically implicated in Alzheimer’s disease progression. Previous research only focused on one region, the prefrontal cortex. Researchers also analyzed over 76,000 nuclei — the centers of the cells that act as control rooms — from the prefrontal cortex, entorhinal cortex, and hippocampus.

“In this study, we wanted to include all three and then compare them to see what signals are consistent and what signals are unique across the three brain regions at the single-cell level. That’s what makes this work significant; it has never been done before for this disease context,” said Andi Liu, PhD, graduate research assistant at UTHealth Houston School of Biomedical Informatics.

According to the study, genes within the entorhinal cortex and hippocampus have the most severe disruptions consistent with their symptomatic involvement in sporadic early onset Alzheimer’s disease. The team discovered malfunctions in genes that act as “switches” for cell behavior. They identified two key gene switches: one in support cells called astrocytes (RFX4) and another in immune cells of the brain called microglia (IKZF1). These switches control genes that affect how brain cells communicate and how the brain’s immune system responds. They found that cell pathways used for maintaining neuroinflammation and junctions where neurons communicate using electrical or chemical signals were altered in the presence of Alzheimer’s pathogens. The study also investigated glial cells, which support brain cells, and astrocytes, which produce inflammation to kill bacteria and viruses but may accidentally kill brain cells when responding to amyloid plaques.

While some of the findings are aligned with late-onset Alzheimer’s disease progression, they found that sporadic early onset Alzheimer’s disease showed unique patterns, including shared vulnerabilities with conditions like schizophrenia and bipolar disorder. The study highlights potential therapeutic targets for doctors, who can then aim at restoring normal gene regulation and intercellular communication, paving the way for precision approaches in Alzheimer’s disease research.

“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.” He holds the Rick McCord Professorship in Neurology and the Umphrey Family Professorship in Neurodegenerative Diseases at the medical school, and he also serves as director of the UTHealth Houston Neurosciences Neurocognitive Disorders Center.

Additional authors from the School of Public Health include Liu and Nitesh Enduru, MPH, in the Department of Epidemiology. From the Center for Precision Health at McWilliams School of Biomedical Informatics: Citu Citu, PhD; Xian Chen, PhD; Chia-Hao Tung, PhD; Astrid M. Manuel, PhD; Brisa S. Fernandes, MD, PhD; Meifang Yu, PhD. From the Department of Neurology at McGovern Medical School: Schulz; Tirthankar Sinha, PhD; Sofia E. Sepulveda, PhD; Damian Gorski, PhD; Claudio Soto, PhD. Other authors include Lukas M. Simon, PhD, at Baylor College of Medicine.

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