Neurons with amyloid plaques (yellow), a hallmark of Alzheimer’s disease. Credit: NIH
Key points:
- A female member of a large family plagued by Alzheimer’s disease somehow evaded the disease.
- Looking to her for clues, researchers found that she carried two copies of a rare variant of an APOE gene known as the Christchurch mutation.
- Study results show this gene aggressively disposes of tau aggregates—making it a potential target for future Alzheimer’s treatment.
Alzheimer’s disease has plagued one large Colombian family for generations, killing half of its members early in life. But one family member evaded what had seemed like fate: Despite inheriting the genetic defect that caused her relatives to develop dementia in their 40s, she stayed cognitively healthy into her 70s.
Researchers at Washington University School of Medicine in St. Louis now think they know why. A previous study had reported that, unlike her relatives, the woman carried two copies of a rare variant of the APOE gene known as the Christchurch mutation. But with only one person in the world known to have this particular combination of genetic mutations, there was not enough data to prove that the Christchurch mutation was responsible for the woman’s remarkable resistance to Alzheimer’s and not simply a coincidental finding.
For this study, published in Cell, researchers took mice genetically predisposed to overproduce amyloid and modified them to carry the human APOE gene with the Christchurch mutation. Then, they injected a tiny bit of human tau into the mouse brains. Normally, introducing tau into brains already brimming with amyloid seeds a pathological process in which tau collects into aggregates at the site of injection, followed by the spread of such aggregates to other parts of the brain—but not so in the mice with the Christchurch mutation.
Much like the woman, the mice developed minor tau pathology despite extensive amyloid plaques. The researchers discovered that the key difference was the activity levels of microglia, the brain’s waste-disposal cells. Microglia tend to cluster around amyloid plaques. In mice with the APOE Christchurch mutation, the microglia surrounding amyloid plaques were revved up and hyper-efficient at consuming and disposing of tau aggregates.
“These microglia are taking up the tau and degrading it before tau pathology can spread effectively to the next cell,” said senior author David Holtzman, MD, distinguished professor of neurology at Washington University School of Medicine. “That blocked much of the downstream process; without tau pathology, you don’t get neurodegeneration, atrophy and cognitive problems. If we can mimic the effect that the mutation is having, we may be able to render amyloid accumulation harmless, or at least much less harmful, and protect people from developing cognitive impairments.”