Alzheimer’s disease has long haunted a prominent Colombian family, relentlessly targeting half of its members in the prime of their lives. However, in a remarkable turn of events, one family member managed to defy the expected fate.
Despite inheriting the genetic defect responsible for early-onset dementia, she maintained cognitive health well into her 70s. Researchers at Washington University School of Medicine in St. Louis now believe they have uncovered the reason behind this resilience—a rare variant of the APOE gene known as the Christchurch mutation.Â
In a study published in the journal Cell on December 11, scientists used genetically modified mice to shed light on how the Christchurch mutation disrupts the link between the early and late phases of Alzheimer’s disease. Unlike her affected relatives, the woman with the Christchurch mutation accumulated massive amounts of amyloid beta in her brain but remained mentally sharp for decades. This discovery opens the door to a potential new approach to preventing Alzheimer’s dementia.Â
The lead author, David M. Holtzman, MD, the Barbara Burton and Reuben M. Morriss III Distinguished Professor of Neurology, emphasizes the significance of identifying protective factors, stating, “Any protective factor is very interesting because it gives us new clues to how the disease works.” The key lies in understanding the interplay between amyloid beta and tau proteins during the development of Alzheimer’s.Â
Alzheimer’s typically unfolds over about 30 years, with the first two decades characterized by silent progression as amyloid slowly accumulates in the brain. The tipping point occurs when amyloid levels reach a critical threshold, initiating a cascade of destructive processes. Tau proteins form tangles, brain metabolism slows down, and cognitive decline becomes apparent. This pattern holds true for both genetic and non-genetic forms of Alzheimer’s.Â
The Colombian family in question carries a mutation in the presenilin-1 gene, causing accelerated amyloid buildup in their brains starting in their 20s. This rapid accumulation leads to cognitive decline in middle age. However, the woman with the Christchurch mutation stood out—having more amyloid in her brain in her 70s than her relatives did in their 40s, yet showing only minimal signs of cognitive impairment.Â
The study aims to answer a crucial question in Alzheimer’s research: why does amyloid accumulation trigger tau pathology? The woman’s unique case suggested a possible link between the Christchurch mutation and the relationship between amyloid and tau. To investigate further, researchers turned to genetically modified mice.Â
By introducing the human APOE gene with the Christchurch mutation into mice predisposed to overproduce amyloid, the scientists observed a fascinating outcome. Even when tau was injected into the mouse brains, mimicking the conditions that usually lead to tau pathology, the mice with the Christchurch mutation exhibited minimal tau pathology despite extensive amyloid plaques. The key difference was found in the activity levels of microglia, the brain’s waste-disposal cells.Â
Microglia surrounding amyloid plaques in mice with the APOE Christchurch mutation were highly efficient at consuming and disposing of tau aggregates, preventing the spread of tau pathology. Holtzman notes, “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.”Â
The discovery of the Christchurch mutation’s protective effects opens a promising avenue for developing strategies to halt or mitigate Alzheimer’s progression. Understanding the intricate relationship between amyloid and tau and harnessing the potential of microglia may pave the way for groundbreaking therapeutic interventions in the battle against Alzheimer’s disease.Â
Journal Reference Â
Yun Chen et al, APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread, Cell (2023). DOI: 10.1016/j.cell.2023.11.029Â
