New Study Unveils Gene Control Breakdown in Alzheimer’s Disease

A groundbreaking study published in the journal Cell on September 4, 2023, by researchers at the Massachusetts Institute of Technology (MIT), reveals critical insights into the mechanisms of Alzheimer’s disease. The research highlights how Alzheimer’s erodes the ability of brain cells to control gene expression, which is essential for maintaining cognitive function.

This comprehensive study presents a multimodal atlas that spans 3.5 million cells from six brain regions, analyzing 384 post-mortem brain samples from 111 donors. The researchers employed advanced profiling techniques to examine both the “transcriptome,” which reflects gene expression, and the “epigenome,” which indicates how DNA is modified and regulated across different cell types.

The findings indicate that Alzheimer’s progression is marked by two significant epigenomic trends. First, vulnerable cells in key brain regions experience a breakdown in their nuclear compartments, which are critical for regulating gene expression. Second, these cells suffer a loss of “epigenomic information,” which impairs their specific identity and function.

Understanding Gene Expression in Alzheimer’s

The study’s lead authors, Zunpeng Liu and Shanshan Zhang, utilized a combination of single-cell RNA sequencing and ATAC-seq to assess gene expression and chromosomal accessibility. This approach allowed them to explore the gene regulation mechanisms across seven broad classes of brain cells and 67 subtypes. They discovered that the erosion of epigenomic markings directly correlates with the loss of cognitive function.

For instance, in individuals who advanced to late-stage Alzheimer’s, compartments that typically repress gene expression became more active, leading to increased expression of disease-related genes. Liu noted, “For Alzheimer’s patients, repressive compartments opened up, and gene expression levels increased, which was associated with decreased cognitive function.”

The study also revealed that when cells maintain their epigenomic stability, individuals retain cognitive abilities. This highlights the importance of understanding how epigenomic conditions affect neuronal health.

Pathways to New Alzheimer’s Treatments

The research underscores the potential for developing new treatments that target the underlying factors responsible for the breakdown of epigenomic control. According to senior author Manolis Kellis, “This is the first large-scale, single-cell, multi-region gene-regulatory atlas of Alzheimer’s disease, systematically dissecting the dynamics of epigenomic and transcriptomic programs across disease progression and resilience.”

The study also examined the role of specific genes in Alzheimer’s pathology. For example, the APOE gene, particularly the e4 variant, is recognized as a significant genetic risk factor for the disease. The research indicated that microglia, which initially respond to disease pathology with increased epigenomic information, ultimately experience a decline as the disease progresses.

The findings provide a framework for further exploration of how epigenomic factors drive Alzheimer’s progression. Co-author Li-Huei Tsai, a professor at MIT and director of The Picower Institute for Learning and Memory, stated, “The key to developing new and more effective treatments for Alzheimer’s disease depends on deepening our understanding of the mechanisms that contribute to the breakdowns of cellular and network function in the brain.”

This study sheds light on the intricate relationship between gene regulation and Alzheimer’s disease, offering hope for future therapeutic strategies that could improve the lives of those affected by this debilitating condition.