When one member of a large Colombian family, plagued by Alzheimer’s disease for generations, evaded the disease (staying cognitively healthy into her 70s) despite inheriting the genetic mutation that caused her relatives to develop dementia in their 40s,  researchers sought to understand why.

The Colombian patient carried the presenilin-1 mutation. Generally, people with a presenilin-1 mutation (PSEN1-E280A) develop amyloid buildup beginning in their 20s, accumulate amyloid quickly, and typically start showing signs of cognitive decline in middle age. However, the patient was also a homozygous carrier of the APOE3 Christchurch (APOE3ch) mutation which is thought to provide resistance to Alzheimer’s disease.

“One of the biggest unanswered questions in the Alzheimer’s field is why amyloid accumulation leads to tau pathology,” said David Holtzman, MD, professor of neurology at Washington University School of Medicine. “This woman was very, very unusual in that she had amyloid pathology but not much tau pathology and only very mild cognitive symptoms that came on late. This suggested to us that she might hold clues to this link between amyloid and tau.”

In a new study, researchers used genetically modified mice to show that the Christchurch mutation severs the link between the early phase of Alzheimer’s disease, amyloid beta builds up in the brain, and the late phase, when tau accumulates and cognitive decline sets in.

This work is published in Cell in the paper, “APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread.

In this case, the woman stayed mentally sharp for decades, despite amyloid buildup. “Any protective factor is very interesting, because it gives us new clues to how the disease works,” said Holtzman. “As people get older, many begin to develop some amyloid accumulation in their brains. Initially, they remain cognitively normal. However, after many years the amyloid deposition begins to lead to the accumulation of the tau protein. When this happens, cognitive impairment soon ensues. If we can find a way to mimic the effects of the APOE Christchurch mutation, we may be able to stop people who already are on the path to Alzheimer’s dementia from continuing down that path.”

To experiment with this, researchers generated a humanized APOE3ch knock-in mouse and crossed it to an amyloid-β (Aβ) plaque-depositing model. They then injected human tau into the brains of the mice. Typically, introducing tau into brains 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.

This was not the result with the mice with the Christchurch mutation. Much like the Colombian patient, the mice developed minor tau pathology despite extensive amyloid plaques. The authors wrote, “Similar to the case report, APOE3ch expression resulted in peripheral dyslipidemia and a marked reduction in plaque-associated tau pathology. Additionally, we observed decreased amyloid response and enhanced microglial response around plaques.”

The researchers uncovered that the key difference was the activity levels of microglia, the brain’s waste-disposal cells. The authors noted that, “APOE3ch influences the microglial response to Aβ plaques, which suppresses Aβ-induced tau seeding and spreading.” Microglia tend to cluster around amyloid plaques. In mice with the APOE3ch mutation, the microglia surrounding amyloid plaques were hyperefficient 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,” Holtzman said. “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.”

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