Recent research published in the journal Nature Medicine showcases a remarkable case study funded by the National Institutes of Health (NIH) that sheds light on Alzheimer's disease. The study focuses on the second person known to possess an extraordinary resilience to a rare genetic form of early onset Alzheimer's. This follows a 2019 report of a woman with a similar resistance to developing Alzheimer's symptoms despite having the same strong genetic predisposition for the disease.
The case study centers around a man from Colombia who belongs to a well-studied extended family with a genetic variant known as the "Paisa" mutation. This family is the largest in the world with this mutation, which follows an autosomal dominant pattern of inheritance. Typically, individuals with this variant develop mild cognitive impairment around the age of 44, progress to dementia by age 50, and have a life expectancy of around 60, in contrast to the more common form of Alzheimer's that usually begins after the age of 65.
Led by a team including researchers Yakeel Quiroz, Joseph Arboleda-Velasquez, Diego Sepulveda-Falla, and Francisco Lopera, the study highlights a Colombian man who showed cognitive resilience despite carrying the Paisa mutation. At the age of 67, he displayed intact cognitive function and only experienced mild cognitive impairment at 70, more than 20 years later than expected. At 73, he joined the Colombia-Boston biomarker research study (COLBOS), which involved neuroimaging tests to identify Alzheimer's hallmarks, such as amyloid plaques and tau tangles.
Although the man eventually succumbed to Alzheimer's at 74, researchers are intrigued by his prolonged resilience. While a previous study identified a woman with a protective genetic variant called Christchurch, the man did not possess this variant. However, through genomic analysis, the researchers discovered a novel gene variant they named Reelin-COLBOS. This gene encodes a protein that controls signals to chemically modify tau proteins, which are implicated in Alzheimer's-related memory loss. Reelin is functionally linked to APOE, the gene altered in the woman with remarkable Alzheimer's protection. Both Reelin and APOE interact with common protein receptors in neurons, reinforcing the significance of tau-related signaling pathways in Alzheimer's progression and resilience.
Further clues were gleaned from neuroimaging exams conducted when the man was 73. They revealed extensive amyloid plaques and tau tangles in several brain regions, except for the entorhinal cortex, a vital area for memory and cognitive function. Notably, the entorhinal cortex exhibited minimal tau tangles. Studies on Alzheimer's mouse models confirmed that the Reelin-COLBOS variant reduces the pathological modifications of tau, providing additional support for the protective role of this variant.
Overall, these findings emphasize the potential of the Reelin pathway and the entorhinal cortex as promising targets for future research and the development of Alzheimer's treatments. The researchers are actively exploring treatment approaches inspired by the Christchurch and Reelin-COLBOS discoveries.
While additional research on these individuals and others like them is needed, these findings offer encouraging prospects for individuals at risk of Alzheimer's disease. They underscore the importance of studying exceptional individuals to unravel the complexities of the disease and drive biomedical breakthroughs.
