Alzheimer's disease may not solely be attributed to the buildup of plaques, but rather an epigenomic deterioration as well.

A groundbreaking study has shed light on the intricate workings of Alzheimer's disease (AD), revealing critical insights into its progression and cognitive resilience. The research, which presents a comprehensive single-cell multiomic atlas, has uncovered widespread epigenome relaxation and brain-region-specific and cell-type-specific epigenomic erosion signatures during AD progression.

At the heart of this study lies the discovery of a turnabout in cell behaviour as the disease advances. Resilient cells express genes promoting neural connectivity, a sign of their adaptability and survival. However, epigenomically eroded cells, particularly those in individuals with two copies of the APOE4 gene, express genes linked to inflammation and oxidative stress, indicating their deterioration and degeneration.

The e4 variant of the APOE gene is the single biggest genetic risk factor for Alzheimer's. In APOE4 brains, microglia, the immune cells of the brain, exhibit a sharp drop off in information as the disease progresses, a sign of their exhaustion. Interestingly, these microglia initially respond to the emerging disease pathology with an increase in their epigenomic information.

In contrast, cells that remain resilient, such as RELN-expressing neurons, maintain their epigenomic information. However, neurons expressing the gene RELN and its protein Reelin exhibit early and severe epigenomic information loss as the disease advances. This loss of epigenetic control is more pronounced in APOE4 brains.

The findings suggest that APOE4 might destabilise the genome of microglia, causing them to burn out. Cells with greater epigenomic erosion and advanced AD progression display increased chromatin accessibility in areas that were supposed to be locked down by Polycomb repression genes or other gene expression silencers.

Despite the significant advancements made, further research is needed to identify the specific brain cells that lose their epigenetic control during Alzheimer's disease. This knowledge could pave the way for more targeted treatments and a better understanding of the disease's complexities.

In conclusion, this study offers a significant step forward in our understanding of Alzheimer's disease, providing valuable insights into its progression and the role of epigenetic changes in cognitive resilience. The findings could potentially lead to more effective strategies for managing and treating this debilitating condition.

Alzheimer's disease may not solely be attributed to the buildup of plaques, but rather an epigenomic deterioration as well.