In the 18th century, a man – probably from Spain – brought a mysterious disease to what is now the Antioquia region of Colombia. This individual had a unique genetic mutation—not present in previous generations—that condemned him to an unenviable fate: sudden memory loss around age 44 and early Alzheimer’s disease around age 49. Today about 6,000 descendants of this man live in Antioquia. and 1,200 of them carry this mutation, known as E280A or Paisa. Early dementia is so common that it has popular names in some villages, such as “la bobera” after the Spanish word for fool.
On Monday, a team of scientists presented the exceptional case of a man who was a carrier of the mutation but only developed cognitive impairment at the age of 67. His name is Patient J. He started developing Alzheimer’s at age 72, more than two decades later than expected. Researchers believe his case opens the door to new avenues in finding an effective treatment for the disease.
Colombian neuropathologist Diego Sepúlveda received the donated brain of patient J in his laboratory at the University Hospital Hamburg-Eppendorf in Germany in late 2019. The man had died at the age of 74 from aspiration pneumonia, a common infection in people who have dementia and have difficulty swallowing Suffer. In the brains of Alzheimer’s patients, plaques of beta-amyloid, a protein that clumps between neurons, and tangles of tau, another protein that accumulates in brain cells, are common. However, Sepulveda’s team got a surprise. The brain of the deceased contained amyloid beta, but there were few tau tangles in the entorhinal cortex, one of the first areas affected in Alzheimer’s disease. The researchers believe this resistance to early dementia stems from another protective mutation, which they named COLBOS, an acronym for Colombia and Boston, where most of the authors are from.
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Patient J is the second known person to be a carrier of the E280A mutation and not have early Alzheimer’s disease. The first was Aliria Rosa Piedrahita de Villegas, who died in 2020 at the age of 77 in the Colombian city of Medellín after being diagnosed with dementia three decades later than expected. Piedrahita de Villegas had a protective mutation called Christchurch in the apolipoprotein E gene that is linked to the risk of Alzheimer’s.
In this second case, the researchers discovered a mutation in the gene that expresses Reelin, a protein that competes with apolipoprotein E for binding to the same receptors in brain cells. When Reelin binds, the tau entanglements associated with Alzheimer’s disease decrease. When apolipoprotein E binds, they increase.
Sepulveda emphasizes that the mutations in both cases may have common cellular effects, but the big difference is in the expression of each protein. “The brain swims in apolipoprotein E, we express it in relatively large amounts and in many parts, while in adults Reelin is expressed only slightly and in very specific cells.” Our finding tells us that this local effect is sufficient to prevent the onset of the delaying the disease by several decades,” explains the neuropathologist.
“In terms of therapy, what it means for us is that we can try to mimic this localized effect, apparently in the entorhinal cortex. Perhaps in the future we will know that some cases benefit from global therapy throughout the brain, while in other cases it is enough to protect only that specific region,” he adds. His findings were published in the journal Nature Medicine on Monday.
Francisco Lopera from the University of Antioquia in Medellín at his home in Itagüí.Santiago Mesa
According to the World Health Organization, more than 55 million people worldwide suffer from some form of dementia, with Alzheimer’s accounting for around 70% of cases. Lead authors of the new study include Francisco Lopera, the neurologist who began analyzing early cases of dementia in Colombia more than 30 years ago. His team from the University of Antioquia in Medellín studied more than 6,000 members from 25 families, focusing on one city: Yarumal, which has become a genetic island due to its centuries-long isolation. According to Lopera, “the secret against the disease” could be hidden there.
Lopera met Patient J and says he lived normally until he was 67. “What Aliria and J teach us is that disease and healing coexist in nature. We just have to read nature and imitate it. If we succeed, we can delay Alzheimer’s disease by 20 to 30 years,” says Lopera. The Colombian neurologist suggests two possible treatments: developing molecules that mimic the effects of these protective mutations, and modifying DNA through gene therapies delivered into the brain using a virus.
Neuroscientist Immaculate Knife welcomes the new study but remains cautious. “Due to the novelty and rarity of subjects carrying this mutation, it is too early to derive potential therapeutic avenues from the results of this article,” says Cuchillo, professor at the Institute of Neurosciences in Alicante, Spain.
In her laboratory, Cuchillo studied the Reelin protein in the tissues of people with Alzheimer’s and discovered changes that would impair its protective function. “This mutation appears to have a greater positive effect on tau in the entorhinal region of the brain, which is very interesting as this is the region where the progressive accumulation of tau entanglements in Alzheimer’s disease begins.” This suggests suggests that this is why it protects against cognitive impairment even though tau and beta-amyloid continue to accumulate in the rest of the brain,” says Cuchillo.
Diego Sepúlveda (left) with colleagues Nelson Villalba and Lisa Littau at the University Medical Center Hamburg-Eppendorf, Germany. Mohsin Shafiq
The researcher compares the new mutation COLBOS to the Christchurch mutation carried by Aliria Rosa Piedrahita de Villegas. “Both mutations are protective against Alzheimer’s disease, and while the effects on tau and beta-amyloid accumulation are not the same, the proteins they express – Reelin and apolipoprotein E – bind to the same cell receptor, ApoER2, which has been studied extensively.” was made.” Our laboratory. This suggests that this receptor and the signaling cascade that starts after its activation may play a key role in Alzheimer’s disease,” argues Cuchillo.
The fight against Alzheimer’s disease has so far focused – with little if any success – on trying to reduce the buildup of beta-amyloid and tau proteins in the brain, which lead to neuron death.
“It’s possible that treatment focused on increasing function or Reelin levels may be the key to finding a therapy for Alzheimer’s, but considering Reelin’s primary roles in nervous system and neurodevelopment neural connection, we have to be.” Be careful,” warns Moreno. “The function of this molecule is finely tuned: both low and high concentrations can be harmful.”
Colombian neuropsychologist Yakeel Quiroz of Massachusetts General Hospital in the United States co-directed the research on Patient J. She is also optimistic about the study. “Our findings on this exceptional case open new doors for the development of Alzheimer’s therapies,” she says.
Her Harvard Medical School colleague Joseph Arboleda founded Epoch Biotech, which is trying to develop treatments that target Alzheimer’s-resistant patients. “Current drugs offer very limited benefits. Our patients have been protected for more than 20 years and we hope that new therapies will do the same,” he notes.
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