Researchers at Washington University School of Medicine have identified a rare APOE gene variant known as the Christchurch mutation, which appears to sever the link between early amyloid beta accumulation in the brain and the subsequent development of tau protein and cognitive decline in Alzheimer’s disease.
The study suggests that individuals with this mutation may remain cognitively healthy despite significant amyloid buildup for decades.
The findings could lead to new approaches for preventing Alzheimer’s dementia by mimicking the protective effects of the Christchurch mutation.
Alzheimer’s disease develops over approximately 30 years, with the initial two decades characterized by silent amyloid accumulation in the brain.
When cognitive decline becomes evident, the tipping point marks the start of destructive processes involving tau protein tangles, brain metabolism slow down, and brain shrinkage.
The Christchurch mutation was identified in a Colombian woman who displayed extensive amyloid buildup in her 70s but minimal signs of brain injury and cognitive impairment.
The study utilized genetically modified mice with the Christchurch mutation in the APOE gene. When these mice were introduced to human tau, they displayed minor tau pathology despite extensive amyloid plaques.
This outcome was attributed to the hyperactive microglia, brain waste-disposal cells, and surrounding amyloid plaques in mice with the APOE Christchurch mutation.
These microglia efficiently cleared tau aggregates, preventing the downstream processes that lead to neurodegeneration, atrophy, and cognitive issues.
The findings offer insights into potential interventions that could render amyloid accumulation less harmful and protect individuals from developing cognitive impairments associated with Alzheimer’s disease.
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The research findings can be found in Cell.
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