Study Reveals How APOE Isoforms Impact Brain Microglia

A recent study in Nature Communications provides insight into how APOE isoforms alter human microglia activity in Alzheimer’s disease. The study, led by Dr. Sarah Marzi and Dr. Kitty Murphy of the UK Dementia Research Institute at King’s and the Department of Basic and Clinical Neuroscience, emphasizes the need for innovative targeted interventions based on APOE genotypes.

Alzheimer’s disease is the leading cause of dementia in the UK, affecting one in every 14 people over the age of 65. It is characterized by the accumulation of proteins in the brain in the form of amyloid plaques and tau tangles.

The APOE gene is a major genetic risk factor for Alzheimer’s. It exists in three common variants: APOE2, APOE3, and APOE4. While APOE4 increases the risk of developing the disease, APOE2 is associated with a reduced risk. The mechanisms by which these isoforms confer such different risk profiles have remained unclear.

To investigate this, researchers focused on APOE’s role in microglia—the brain’s immune cells, which have been increasingly linked to Alzheimer’s pathology. Because the three human APOE variants are evolutionarily distinct and not naturally found in mice, directly studying them in a mouse brain poses challenges.

To overcome this, the team developed a human xenotransplantation model. They generated human microglia from stem cells and engineered them to express one of the APOE variants. These microglia were then transplanted into mice with amyloid plaque accumulation. Following transplantation, the microglia were isolated and analyzed for gene expression (using transcriptomics) and chromatin accessibility.

The study revealed widespread changes in both gene expression and chromatin structure depending on the APOE variant expressed. The most pronounced differences were observed between APOE2 and APOE4 microglia.

Microglia expressing APOE4 produced higher levels of cytokines—molecules that regulate immune responses. These cells also exhibited impaired migration and a reduced ability to enter protective states. Additionally, their phagocytic function—the capacity to clear debris and pathogens—was diminished.

In contrast, APOE2-expressing microglia showed increased expression of genes linked to microglial proliferation and migration, along with a reduced inflammatory response. Notably, these cells also demonstrated enhanced binding of the vitamin D receptor to DNA. Low vitamin D levels have previously been associated with increased Alzheimer’s risk.

The findings show that microglial responses to amyloid pathology vary significantly depending on APOE genotype. This highlights the importance of considering both genetic risk factors and microglial states in understanding disease progression. The study also points to a potential role for the vitamin D receptor in Alzheimer’s, suggesting new avenues for therapeutic exploration.

Our findings emphasise that there is a complex interplay between genetic, epigenetic, and environmental factors that influence microglial responses in Alzheimer’s disease. We found remarkable differences when comparing microglia expressing different isoforms of the same gene.

Dr. Sarah Marzi, Study Lead and Senior Lecturer, Neuroscience, King's College London

Dr. Marzi concluded, “Our research suggests that microglia expressing the risk-increasing APOE4 variant are not as effective at mounting protective microglial functions, including cell migration, phagocytosis, and anti-inflammatory signalling. This underscores the need for targeted interventions based on APOE genotype.”