APOE Isoforms Influence Microglia Differently in Alzheimer's Disease

A new study, published today in Nature Communications, offers clues into how APOE isoforms differentially affect human microglia function in Alzheimer's disease. The study, led by Dr Sarah Marzi and Dr Kitty Murphy at the UK Dementia Research Institute at King's and the Department of Basic and Clinical Neuroscience, underscores the need for new targeted interventions based on APOE genotypes.

Alzheimer's disease is the most common cause of dementia in the UK, affecting 1 in 14 people over the age of 65. Alzheimer's is characterised pathologically by a buildup of proteins in the form of amyloid plaques and tau tangles.

The apolipoprotein E (APOE) gene is a major genetic risk factor for Alzheimer's disease. There are three different versions of the APOE protein: APOE2, APOE3, and APOE4. While APOE4 increases the risk of developing Alzheimer's, APOE2 is associated with a lower risk. However, how these isoforms lead to strikingly different risk profiles is poorly understood.

In this study, researchers looked at APOE in microglia, the brain's immune cells known to play a role in Alzheimer's disease. As the three versions of APOE are evolutionarily unique to humans, they can't be directly studied in a mouse brain, posing a challenge to studying them in a laboratory setting.

To overcome this, researchers developed a human "xenotransplantation model". This is where human microglia were grown from stem cells, manipulated to express different APOE versions, then transplanted into the brains of mice that had developed a buildup of amyloid plaques. The microglia were then isolated and analysed for their gene expression (using a technique called transcriptomics) and for their chromatin accessibility (how accessible the DNA is for genes to be expressed).

The researchers uncovered widespread changes to the transcriptomic and chromatin landscape of microglia, dependent on the APOE isoform expressed. The largest differences were observed when comparing the APOE2 and APOE4 microglia.

In APOE4 microglia, researchers saw an increase in the production of cytokines, signalling molecules involved in immune regulation. They also observed diminished capacity for the microglia to migrate and shift into protective states. Furthermore, the microglia became less effective in phagocytosis, a process by which they digest and clear up particles such as debris and pathogens.

Conversely, APOE2 microglia showed increased expression of various genes that increase microglia proliferation and migration, and a decreased inflammatory immune response. Additionally, APOE2 microglia showed increased DNA-binding of the vitamin D receptor. Low levels of vitamin D have been associated with a higher incidence of Alzheimer's.

The study highlights that microglia responses to amyloid pathology differ significantly across APOE versions. This finding underscores that considering the interplay between genetic risk factors and microglial states is critical in disease progression. The study also highlights the potential role of the vitamin D receptor, providing new avenues for therapeutic exploration.

Reference: Murphy KB, Hu D, Wolfs L, et al. The APOE isoforms differentially shape the transcriptomic and epigenomic landscapes of human microglia xenografted into a mouse model of Alzheimer’s disease. Nat Commun. 2025;16(1):4883. doi: 10.1038/s41467-025-60099-4

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