Some people may be genetically protected from Alzheimer’s

The researchers used induced human stem cells (these are stem cells derived from somatic, reproductive, or pluripotent cells through epigenetic reprogramming) that were genetically modified to isolate the effects of different forms of APOE. A comparative analysis of the neurons revealed that cells with the APOE2 variant had increased DNA repair efficiency. These neurons actively regulated the metabolic pathways involved in the restoration of genetic material and exhibited a robust response to external damage. Direct measurements of DNA strand breaks have confirmed that the accumulation of genetic defects is significantly slower in cells with APOE2 than in neurons with other isoforms of this protein.

In addition to their ability to repair, neurons with APOE2 exhibit increased resistance to cellular aging, known as senescence. When exposed to stress factors such as ionizing radiation or chemotherapy agents, these cells maintain their nuclear architecture and exhibit reduced levels of specific aging markers. The experiments also revealed the possibility of transferring this protective effect: adding recombinant APOE2 protein to the medium of neurons with the APOE4 variant reduced the intensity of DNA damage signals, indicating the potential therapeutic use of this protein to neutralize negative genetic factors.

Analysis of the hippocampus tissues of aging mice confirmed the data obtained during the in vitro experiments. Individuals carrying the APOE2 gene had more preserved heterochromatin and increased levels of the protein lamin A/C, which provides structural support for the cell nucleus. Accumulation of DNA damage and transition of cells to the state of cellular aging are critical mechanisms of neurodegeneration in Alzheimer’s disease. The results obtained suggest that strategies aimed at activating DNA repair processes or eliminating aging cells can mimic the natural protection provided by APOE2. In further studies, it is planned to clarify the molecular mechanisms of nuclear envelope stabilization and to search for mimetic compounds capable of providing similar protection to carriers of the APOE4 variant, which is the most significant genetic risk factor for the development of the late form of Alzheimer’s disease.