Signs of Alzheimer’s prevention from the patient who, despite the genetics, avoided the disease | Washington University School of Medicine in St. Louis

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Breaking the link between early, late stages of the disease may prevent dementia

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Alzheimer’s disease has plagued a large family in Colombia for generations, killing half of its members in the prime of life. But one family member avoided what seemed like fate: Despite inheriting a genetic defect that caused his relatives to develop dementia in their 40s, he remained mentally healthy into his 70s.

Researchers at Washington University School of Medicine in St. Louis now thinks they know why. A previous study reported that, unlike her relatives, the woman carried two copies of a rare variant of APOE gene known as the Christchurch mutation. In this study, researchers used genetically modified mice to show that the Christchurch mutation breaks the link between the early stage of Alzheimer’s disease, when a protein called amyloid beta builds up in the brain, and the late stage. , when another protein called tau accumulates and cognitive decline begins. So the woman remained mentally sharp for decades, even though her brain was filled with a lot of amyloid. The findings, published on December 11 in the journal Cell, suggest a new method of preventing Alzheimer’s dementia.

Any protective factor is very interesting, because it gives us new clues about how the disease works, said senior author David M. Holtzman, MD, Barbara Burton and Reuben M. Morriss III. Distinguished Professor of Neurology. As people get older, many begin to develop some amyloid accumulation in their brain. At first, they remain mentally normal. However, after many years amyloid deposition begins to lead to accumulation, aggregation of tau protein. When this happens, cognitive impairment soon follows. If we can find a way to replicate the effects of APOE Christchurch mutation, we can prevent people who are already on the road to Alzheimers dementia from continuing on that road.

Alzheimer’s develops over about 30 years. The first two decades or so were quiet; Amyloid slowly accumulates in the brain without causing any adverse effects. When amyloid levels reach a tipping point, however, it begins a second phase, which involves several interrelated destructive processes: A protein called tau forms tangles that spread in the brain; brain metabolism slows down, and the brain begins to shrink; and people begin to experience problems with memory and thinking. The disease follows the same pattern in people with both genetic and nongenetic forms of Alzheimers.

Colombian families have a mutation in a gene called presenilin-1 which causes their brains to develop a lot of amyloid buildup starting in their 20s. People who carry the mutation accumulate amyloid that quickly reaches a tipping point and begins to show signs of cognitive decline in middle age. A rare exception was a woman who had more amyloid in her brain at age 70 than her relatives at age 40, but fewer signs of brain damage and cognitive impairment.

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

A 2019 study revealed that, along with a mutation in the presenilin-1the woman also carries the Christchurch mutation in two copies of her APOE gene, another gene associated with Alzheimer’s disease. But with only one person in the world known to have this particular combination of genetic mutations, there is not enough data to prove that Christchurch’s mutation is responsible for his remarkable resistance to Alzheimers and not a random search.

To solve this puzzle, Holtzman and first author Yun Chen, a graduate student, turned to genetically modified mice. They took mice that were genetically predisposed to overproduction of amyloid and modified them to carry it in humans APOE gene with the Christchurch mutation. Then, they injected small amounts of human tau into the mice’s brains. Generally, the introduction of tau into brains already full of amyloid seeds is a pathological process in which tau collects in aggregates at the injection site, followed by the spread of such aggregates to other parts of the brain. .

Not so in mice with the Christchurch mutation. Like the Colombian woman, the mice developed minor tau pathology despite large amyloid plaques. The researchers discovered that the key difference was the level of activity of microglia, the brain’s waste disposal cells. Microglia tend to cluster around amyloid plaques. In mice with APOE In the Christchurch mutation, the microglia that surround amyloid plaques are altered and become more efficient at consuming and disposing of tau aggregates.

These microglia take up tau and degrade it before tau pathology can effectively spread to the next cell, Holtzman said. That hinders most of the process below; Without tau pathology, you don’t get neurodegeneration, atrophy and cognitive problems. If we can mimic the effect of the mutation, we can make amyloid accumulation harmless, or at least less harmful, and protect people from cognitive impairment.

Chen Y, Song S, Parhizkar S, Lord J, Zhu Y, Strickland MR, Wang C, Park J, Tabor GT, Jiang H, Li K, Davis AA, Yuede CM, Colonna M, Ulrich JD, Holtzman DM. APOE3ch modulates the microglial response and prevents A-induced tau spreading and spreading. Cell. December 11, 2023. DOI: 10.1016/j.cell.2023.11.029

This study was supported by the JPB Foundation; Cure Alzheimer’s Fund; the National Institutes of Health (NIH), grant numbers RF1AG047644 and RF1NS090934; and the Alzheimer’s Association, grant number AARF-21-850865. This content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Holtzman is an inventor on a patent licensed to Washington University by C2N Diagnostics on the therapeutic use of anti-tau antibodies; co-founded and is on the scientific advisory board of C2N Diagnostics; is on the scientific advisory board of Denali, Genentech, and Cajal Neuroscience; consultant for Asteroid; and is on the Advisory Board for the Cell. Colonna is a member of the Vigil Neuro scientific advisory board and a consultant for Cell Signaling Technology and NGM Bio. The other authors have no conflicts of interests.

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WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with 2,800 faculty members. The research funding portfolio of the National Institutes of Health (NIH) is the third largest among US medical schools, has grown 52% in the past six years, and, along with institutional investment, WashU Medicine is committed to more of $1 billion annually in basic and clinical research innovation and training. Its faculty practice is consistently among the top five in the country, with more than 1,800 faculty physicians practicing in 65 locations and who are also medical staff at Barnes-Jewish and St. Louis Children at BJC HealthCare. WashU Medicine has a history of training MD/PhD, recently dedicated $100 million in scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology. and communication science.


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