By Simon Spichak, MSc | September 19, 2022
His brain had all the signs of Alzheimer’s. She never made it. What can it teach us?
Scientists examine the curious case of a woman with genes for early-onset Alzheimer’s who never developed the disease. In an autopsied brain, they found a mutation in the APOE3 gene that could be the key to preventing early-onset forms of the disease.
A small proportion of Alzheimer’s cases are directly related to mutations that cause the accumulation of beta-amyloid proteins and cognitive dysfunction early in life. Aliria Rosa Piedrahita de Villegas, a woman from Colombia, was part of an extended family that carried one of these genetic mutations in a gene called DOG1.
But instead of developing Alzheimer’s in his 40s or 50s as others with this same mutation would, he lived dementia-free into his 70s, dying of a bout of metastatic melanoma in 2020.
He also carried two copies of a mutation in a gene called APOE3, known as a Christchurch mutation. You may have heard of it APOE4, another version of this gene. Transports fat and cholesterol throughout the body. The number of carriers is also increasing Alzheimer’s risk by a factor of two.
Scientists had followed this woman throughout her life and also examined her brain after death in the hope of finding new treatments. They found that although amyloid plaques were present in the brain, as expected due to the PSEN1 gene, they were not located in regions important for memory and complex cognitive tasks. They think the Christchurch mutation might have something to do with it.
“We rarely have pleasant surprises when studying Alzheimer’s disease family brains,” said co-first author Diego Sepulveda-Falla, a physician and head of research at the University Medical Center Hamburg-Eppendorf.
“This patient’s genome has been analyzed extensively over the past four years,” Sepulveda-Falla told Being Patient, adding that it’s the only genetic trait they found that could explain women’s resilience to Alzheimer’s and lead to new treatments.
Finding out why the Christchurch mutation made this woman’s brain so resilient could lead to more successful treatments for early-onset Alzheimer’s. Roche’s anti-amyloid drug crenezumab faltered in a large nine-year prevention study, compounding the efficacy controversy surrounding its predecessor aducanumab (now Aduhelm), and casting more doubt on the beta-amyloid approach.
“This is an innovative case for Alzheimer’s disease and has already opened up new paths of treatment and prevention, which we are currently following with some collaborators,” he added. said Yakeel T. Quiroz, an associate professor at Harvard Medical School and director of the Multicultural Alzheimer’s Prevention Program at Massachusetts General Hospital, who is leading the research. “This work is now shedding light on some of the resistance mechanisms in Alzheimer’s disease.”
The team’s recent findings were published in the newspaper Neuropathological act. Although the woman’s brain had many of the pathological features of Alzheimer’s disease, she remained cognitively healthy. Interestingly, the regions of the brain that tend to accumulate groups of tau proteins in Alzheimer’s: the frontal cortex responsible for complex thinking, and the hippocampus which is responsible for memory and learning — were spared. Instead, tau accumulates in the occipital cortex, which is responsible for visual processing.
The Christchurch APOE3 variant may have influenced where tau proteins formed, as well as stopping the onset of the disease or delaying its severity and progression in a genetic form of Alzheimer’s disease.
When they introduced this mutation into brain cells grown in a dish or animal models of Alzheimer’s, they saw similar protective effects. Sepulveda-Falla said selectively modifying the APOE gene could protect against Alzheimer’s. In addition, studying the APOE3 protein with the Christchurch mutation in the laboratory may help develop drugs that mimic its effects.