New Insights into Alzheimer’s Disease: How It Disrupts Gene Regulation at the Cellular Level

Alzheimer’s disease, widely recognized for its devastating impact on memory and cognitive functions, is now understood to involve complex changes at the molecular level within brain cells. A recent comprehensive study published in the journal Cell by researchers from MIT highlights how the disease fundamentally erodes the control of gene expression in neurons and glial cells, leading to widespread cellular dysfunction.

This groundbreaking research provides a detailed, high-resolution atlas of gene regulation and expression patterns across six brain regions, based on the analysis of 3.5 million cells from 384 post-mortem samples of 111 donors. It combines data on the transcriptome—the set of all expressed genes—and the epigenome—the chromosomal modifications that dictate which DNA regions are accessible for gene expression.

The study reveals two major trends associated with Alzheimer’s progression. Firstly, vulnerable cells in key areas like the entorhinal cortex and hippocampus experience a breakdown of their nuclear compartments, a structure critical for maintaining the proper segregation of active and repressed DNA regions. Secondly, these cells show a loss of epigenomic information, losing their unique gene regulation patterns that define their identity and functionality.

As Alzheimer’s advances, many cells exhibit 'compromised compartmentalization,' where tightly regulated regions of DNA become open or closed inappropriately, leading to abnormal gene expression. For instance, genes associated with disease become overexpressed while those necessary for healthy cell function are silenced. This epigenomic deterioration correlates strongly with cognitive decline, while cells that maintain their epigenomic integrity tend to preserve brain function.

The research emphasizes that Alzheimer’s is not solely about amyloid plaques and neurofibrillary tangles but fundamentally involves the loss of nuclear order and gene regulation. Certain genetic risk factors, such as the APOE4 allele, appear to destabilize the genome of brain immune cells called microglia, accelerating their decline. Neurons expressing the gene RELN, which produce the Reelin protein, are particularly vulnerable but can confer resilience if their epigenomic patterns remain intact.

Overall, the findings suggest that therapeutic strategies aimed at preserving or restoring epigenomic stability in specific brain cell types could be key to combating the disease. Understanding these gene regulatory mechanisms offers a promising path for developing treatments that go beyond traditional approaches focused on pathological proteins.

This study underscores the importance of cellular and molecular resilience in preventing or delaying Alzheimer’s symptoms, providing a critical foundation for future research and targeted therapies.

Source: https://medicalxpress.com/news/2025-09-alzheimer-erodes-brain-cells-gene.html