Clues to preventing Alzheimer’s disease come from patient who evaded disease despite genetic predisposition Washington University School of Medicine in St. Louis

Alzheimer’s disease has plagued a large Colombian family for generations, killing half of its members in their prime. But one member of the family escaped what seemed like fate: Although she inherited a genetic defect that caused her relatives to develop dementia in their 40s, she remained cognitively healthy into her 70s.

Researchers at Washington University School of Medicine in St. Louis now think they know why. A previous study reported that, unlike her relatives, the woman carried two copies of the rare variant. APOE The gene known as the Christchurch mutation. In the study, researchers used genetically modified mice to show that the Christchurch mutation shuts off the early stages of Alzheimer’s disease (when a protein called amyloid beta builds up in the brain) and A link between later stages when another protein called tau builds up and leads to Alzheimer’s disease. Cognitive abilities begin to decline. So even though this woman’s brain was filled with large amounts of amyloid, she remained mentally sharp for decades. The findings, published December 11 in the journal Cell, suggest a new way to prevent Alzheimer’s dementia.

“Any protective factor is very interesting because it provides us with insights into how it works,” said senior author David M. Holtzman, MD, the Barbara Burton and Reuben M. new clues about how the disease occurs. As we age, many people begin to accumulate some amyloid in their brains. Initially, their cognitive abilities remained normal. However, over the years, amyloid deposition begins to lead to a buildup of tau protein. When this happens, cognitive impairment can quickly occur.If we could find a way to simulate the effect APOE With the Christchurch mutation, we may be able to stop those already on the path to Alzheimer’s dementia from continuing on that path.

The onset of Alzheimer’s disease takes approximately 30 years. The first twenty years or so are silent; amyloid slowly accumulates in the brain without causing ill effects. However, when amyloid levels reach a critical point, they initiate a second phase that involves several interrelated damaging processes: A protein called tau forms tangles and spreads in the brain; brain metabolism decreases Slowly, the brain begins to shrink; people begin to have memory and thinking problems. The disease follows the same pattern in people with hereditary and non-hereditary forms of Alzheimer’s.

Colombian family carries a genetic mutation called Presenilin-1 This causes their brains to produce too much amyloid starting in their 20s. People with this mutation accumulate amyloid so quickly that they reach a breaking point and begin to show signs of cognitive decline in middle age. One rare exception was a woman in her 70s who had more amyloid in her brain than her relatives in their 40s but had very mild signs of brain damage and cognitive impairment.

Holtzman said one of the biggest unanswered questions in the Alzheimer’s field is why amyloid accumulation leads to tau pathology. This woman was very, very unusual in that she had amyloid pathology, but not much tau pathology, and only had very mild cognitive symptoms, and they came late. This suggests to us that she may hold clues to the link between amyloid and tau.

A 2019 study showed that as Presenilin-1this woman also carries the Christchurch mutation in both copies of her gene APOE gene, another gene linked to Alzheimer’s disease. But because only one person in the world has this particular combination of genetic mutations, there’s not enough data to prove that the Christchurch mutation is the reason for her remarkable resistance to Alzheimer’s, rather than just a coincidence. discovery.

To solve this problem, Holzman and first author Yun Chen, a graduate student, turned to genetically modified mice. They took mice that were genetically prone to overproducing amyloid and engineered them to carry human amyloid. APOE Gene with the Christchurch mutation. They then injected small amounts of human tau protein into the mouse brains. Typically, the introduction of tau into a brain already filled with amyloid seeds leads to a pathological process in which the tau aggregates into aggregates at the site of injection, and the aggregates then spread to other parts of the brain.

But this was not the case for mice carrying the Christchurch mutation. Much like the Colombian women, these mice developed mild tauopathy despite the presence of large amounts of amyloid plaques. The key difference, the researchers found, was the amount of activity in microglia, the brain’s waste-processing cells. Microglia tend to cluster around amyloid plaques.in mice APOE In the Christchurch mutation, microglia around amyloid plaques rev up and are extremely efficient at consuming and disposing of tau protein aggregates.

These microglia take up tau and degrade it before the tau pathology can effectively spread to the next cell, Holtzman said. This blocks most downstream processes; without tau pathology, you don’t have neurodegeneration, atrophy, and cognitive problems. If we could mimic the effects of mutations, we might be able to make the accumulation of amyloid harmless, or at least much less harmful, and protect people from developing cognitive impairment.