A man, probably a Spaniard, brought a mysterious disease to what is now Antioquia (Colombia) in the 18th century. He had a unique genetic mutation, not present in previous generations, that caused an inevitable fate: sudden memory loss around the age of 44 and early Alzheimer’s disease around the age of 49. It felt like a curse. Today there are about 6,000 offspring in the Antioquia area, 1,200 of which carry this mutation known as E280A or Paisa. Early dementia is so common that it has popular names in some cities, such as “la bobera”. A team of scientists this Monday presented an exceptional case, namely a man with the mutation, but who only suffered cognitive decline at the age of 67. This is Patient J. His Alzheimer’s disease began at the age of 72, more than two decades later than expected. Researchers believe his case will open up a new avenue to finding an effective treatment for the disease.
Colombian neuropathologist Diego Sepúlveda Falla 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, an infection common in people who die due to suffer from dementia with difficulty swallowing. In the brains of Alzheimer’s patients, plaques of amyloid beta, a protein that accumulates between neurons, and tangles of tau, another protein that accumulates in brain cells, are common. However, Sepúlveda’s team was in for a surprise. Amyloid beta was present in the brain of the deceased, but little tau entanglement occurred in the entorhinal cortex, one of the first areas affected in Alzheimer’s. The researchers believe that behind this resistance to early dementia lies another protective mutation, which they named COLBOS, an acronym for Colombia and Boston, where most of the authors originated.
He is the second person known to have the fatal E280A mutation and not have early-stage Alzheimer’s. The first was Aliria Rosa Piedrahita de Villegas, who died in Medellín in 2020 at the age of 77 after falling ill with dementia three decades later than expected. Piedrahita de Villegas had a protective mutation called Christchurch in the apolipoprotein E gene, which 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 the reelin is embedded, the tau entanglements associated with Alzheimer’s decrease. When apolipoprotein E binds, they increase.
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Sepúlveda points out that while the mutations in both cases may have common cellular effects, the big difference is in the expression of each protein. “The brain swims in apolipoprotein E, we express it relatively much and in many parts, while in adults Reelin expresses little and in very specific cells.” “Our finding shows that this local effect is sufficient to delay the onset of the disease by several decades to delay,” 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 this specific region,” he points out. Their findings will be published this Monday in the journal Nature Medicine.
Francisco Lopera, director of the Neuroscience Group at the University of Antioquia, at his home in Itagüí, south of Medellín.Santiago Mesa
According to the World Health Organization, more than 55 million people worldwide suffer from some form of dementia, and Alzheimer’s accounts for about 70% of cases. Lead authors of the new study include Francisco Lopera, the neurologist who began analyzing cases of early 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. There, says Lopera, “the secret against the disease” could be hidden.
Lopera met Patient J and recalls living normally until the age of 67. “What Aliria and J teach us is that disease and healing coexist in nature. You just have to read nature and imitate it. If we succeed, we can delay Alzheimer’s disease by 20 to 30 years,” says the Colombian neurologist. Lopera suggests two possible avenues: designing molecules that mimic the action of these protective mutations, or altering DNA through gene therapies delivered into the brain using viruses.
Neuroscientist Inmaculada Cuchillo welcomes the new study but stresses her caution. “Due to the novelty and rarity of subjects carrying this mutation, it is too early to consider possible therapeutic avenues that emerge from the results of this article,” he says. Cuchillo from the Neuroscience Institute in Alicante studied the Reelin protein in the tissues of people with Alzheimer’s in his laboratory 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 since it is the region where the progressive accumulation of tau tangles begins in Alzheimer’s disease.” suggests that this fact per se protects against cognitive decline, even though tau and beta-amyloid continue to accumulate in the rest of the brain,” Cuchillo muses.
Diego Sepúlveda Falla (left) with his colleagues Nelson Villalba and Lisa Littau at the University Medical Center Hamburg-Eppendorf in Germany. Mohsin Shafiq
The researcher compares the new mutation COLBOS with the Christchurch mutation presented 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 cellular receptor, apoER2, which is extensively reported in our studies.” was examined laboratory. . “This suggests that this receptor and the signaling cascade that begins after its activation could be crucial for Alzheimer’s disease,” argues Cuchillo.
Until now, the fight against Alzheimer’s has focused, with little or no success, on trying to reduce the accumulations of the beta-amyloid and tau proteins in the brain, which lead to the death of neurons, like neurobiologist Inés Moreno from Malaga remembers university. “It is possible that treatment focused on increasing function or Reelin levels may be the key to finding a therapy for Alzheimer’s, but given Reelin’s essential roles in nervous system development and neural connectivity this is necessary.” Be careful,” warns Moreno. The function of this molecule is finely tuned: both low and high concentrations can be harmful.
Colombian neuropsychologist Yakeel Quiroz from Massachusetts General Hospital (USA) co-directed the examination of patient J. She is optimistic. “Our findings on this exceptional case open new doors for the development of therapies against Alzheimer’s,” he says. Harvard Medical School colleague Joseph Arboleda founded Epoch Biotech, which is trying to develop treatments inspired by people with Alzheimer’s resistance. “Current drugs offer very limited benefits. Our patients have been protected for more than 20 years and the hope is that new therapies will do the same,” he emphasizes.
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