A rare genetic variant in a Colombian is associated with greater resistance over time to an early-onset type of hereditary Alzheimer’s, pointing to a molecular pathway that could be used therapeutically to increase resilience to the cognitive decline of the disease.
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The variant was found in a deceased man, who did not have cognitive problems until he was 67 years old, despite being a carrier of a mutation known as Paisa, in the PSEN1 gene, which predisposes him to autosomal dominant Alzheimer’s disease (ADAD), a rare hereditary form. . Paisa carriers typically develop mild cognitive impairment at a mean age of 44, dementia at 49, and die from complications at 60.
A group of Colombian, American and German researchers publish in Nature Medicine the details of this case, located through the Colombia-Boston Biomarker Research Study (Colbos). That group follows an extended family of some 6,000 people with the Paisa variant in Colombia, a population group discovered thirty years ago by Francisco Lopera, director of the Neurosciences Group at the University of Antioquia and co-author of the new study.
The genetic variant now identified and called Reelin-COLBOS occurs in the RELN gene, which encodes the reelin protein, with a fundamental role in regulating the development and function of brain cells.
This man is the second case described in this way with greater resistance to ADAD over time, after that of a woman from the same extended family, described in 2019, although she presented a protective variant of another type.
exceptional cases
Nature did “an exceptional experiment with these subjects: it endowed them with a gene that causes Alzheimer’s and, at the same time, with another gene that protected them from the symptoms of the disease for more than two decades,” Lopera highlighted.
The solution is to “imitate nature by developing therapies that mimic the protection mechanism of these genetic variants in subjects at risk of suffering from the disease,” added the researcher in a statement from Mass General Brigham, a network of hospitals based in Boston. (USA).
The team analyzed clinical and genetic data of some 1,200 people from Colombia who were carriers of the Paisa mutation, in which they identified this man who remained without cognitive impairment until he was 67 years old, progressed to moderate dementia at 72 and died at 74. The team compared this case with that of the woman with another rare genetic variant of the gene that encodes apolipoprotein E (APOE), called Christchurch. That woman remained without cognitive decline nearly thirty years past her predicted age of onset, despite showing evidence of Alzheimer’s in her brain.
Two of the hallmarks of Alzheimer’s are the presence of amyloid beta peptide plaques in the brain and the formation of tau protein tangles.
After comparing the characteristics of both people, the team found that they showed widespread amyloid pathology in the brain. However, there was limited aggregation of the tau protein in the entorhinal cortex, a brain region that is characteristically affected in the early clinical stages of Alzheimer’s.
The researchers suggest that the Reelin-COLBOS variant may be more effective in limiting tau protein aggregation and tangle formation. Although they cannot completely rule out that other factors, including additional genetic variants, may have contributed to the patient’s resistance to symptoms, experimental evidence in preclinical studies strongly implicates that variant.
The team plans to continue their work to identify more protected patients from these Colombian families and also to investigate treatments targeting this protective pathway.
