Published on: May 27, 2025
A new study published today in Nature Communications sheds light on how different APOE isoforms distinctly influence human microglial function in Alzheimer's disease. Led by Dr. Sarah Marzi and Dr. Kitty Murphy at the UK Dementia Research Institute at King's College London and the Department of Basic and Clinical Neuroscience, the research emphasizes the importance of developing genotype-specific treatments.
Alzheimer’s disease, the leading cause of dementia in the UK, affects about one in 14 people over the age of 65. It is pathologically marked by the accumulation of amyloid plaques and tau tangles in the brain.
The APOE gene is a key genetic risk factor for Alzheimer's, with three main variants: APOE2, APOE3, and APOE4. While APOE4 significantly increases disease risk, APOE2 appears to offer protection. However, the mechanisms behind these differences have remained unclear.
In this study, scientists focused on APOE's impact on microglia, the brain's resident immune cells, which are known to play a central role in Alzheimer’s pathology. Since APOE isoforms are uniquely human and cannot be directly studied in mice, the team used an innovative human "xenotransplantation model." They derived human microglia from stem cells, engineered them to express each APOE isoform, and transplanted them into mice with amyloid pathology. These microglia were then examined using transcriptomics and chromatin accessibility analyses.
The results revealed extensive APOE isoform-dependent changes in gene expression and chromatin structure in microglia, with the most pronounced differences between APOE2 and APOE4.
Microglia expressing APOE4 showed elevated production of cytokines—molecules that mediate inflammation—along with impaired mobility, reduced ability to transition into protective states, and decreased efficiency in phagocytosis (clearing cellular debris and pathogens).
In contrast, APOE2-expressing microglia exhibited increased gene expression linked to cell proliferation and migration, along with a lower inflammatory response. Notably, these cells also showed enhanced DNA binding by the vitamin D receptor—a finding of interest given the association between low vitamin D levels and greater Alzheimer’s risk.
Overall, the study demonstrates that microglial responses to amyloid pathology vary greatly depending on APOE genotype. These findings highlight the importance of considering genetic context when studying disease progression and point to the vitamin D receptor as a promising therapeutic target.
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