Researchers have found a rare genetic mutation that provided protection against early-onset dementia in a man that was otherwise at high risk. Furthermore, although the man had only mild cognitive impairment, his brain scan showed the physical manifestations of severe dementia. The finding, published in Nature Medicine, sheds light on the causes of Alzheimer’s disease and has implications for the development of new treatments.
A Rare Protective Mutation
For almost four decades, neurologist Francisco Lopera and his team at the University of Antioquia in Medellín, Colombia, have studied an extended family affected by early-onset Alzheimer’s disease. A genetic variant known as the paisa mutation, present in many family members, causes them to develop dementia in their forties or even earlier. The researchers have studied the genomes and medical histories of approximately 1,200 Colombians with the mutation. During their investigation, however, the researchers also identified a family member who possessed a second, protective genetic mutation that held off the effects of the disease until he was 67 years old.
Surprising Brain Scan Results
Although the man with the additional mutation exhibited mild cognitive impairment, scans of his brain revealed the presence of high levels of amyloid plaques, sticky protein complexes associated with neuronal death and dementia. Additionally, the protein tau, which is also associated with the disease, was found throughout the brain except in the entorhinal cortex, a region involved in memory and navigational skill. In this area, tau levels were lower.
The Role of Reelin
Further investigation revealed that the man possessed a mutation in the gene responsible for producing the protein reelin. Reelin is associated with various brain disorders, including schizophrenia and autism, but its role in Alzheimer’s disease has been largely unknown. To explore this connection, the researchers genetically modified mice to carry the same reelin mutation. The mice exhibited limited clustering of tau protein, suggesting that the mutated reelin gene had a protective effect.
Implications and New Perspectives
The findings call into question the prevailing theory that amyloid plaques are the primary drivers of Alzheimer’s disease. This theory has led to the development of drugs designed to remove amyloid, which have resulted in moderate improvements in rates of cognitive decline. However, the study participant with the protective mutation remained mentally healthy while exhibiting high levels of amyloid plaques. This hints at the greater complexity behind Alzheimer’s disease. Researchers suggest that there may be multiple subtypes of the disease, some of which may not be driven by amyloid alone. “We do need different pathways to really finally deal with this disease,” said Yadong Huang, a neurologist at the Gladstone Institutes in San Francisco, California.
The connection between reelin and tau offers promising avenues for new therapies. Currently, clinical trials are evaluating treatments targeting tau. Lopera’s team is now searching for the reelin mutation and other related mutations in individuals with the paisa mutation. The study also highlights the shared mechanisms between reelin and a protein called apolipoprotein E (APOE), associated with Alzheimer’s disease in people without the paisa mutation. Understanding these shared mechanisms could lead to more effective therapies for late-onset Alzheimer’s cases, which progress more slowly and less aggressively than the early-onset type.
Brain Adaptation and Future Research
Although the man’s hippocampus, a brain region involved in learning and memory, showed signs of degeneration, his cognitive abilities were only mildly impaired. This suggests that other parts of the brain may have compensated for the damage, hinting at potential future treatment approaches. Further research is necessary to unravel the specific mechanisms by which reelin and APOE affect tau and whether targeting these proteins could benefit people with Alzheimer’s disease who do not possess the paisa mutation.
“This is one of those few cases that really opens the door for anti-Alzheimer’s research,” said Huang. “The vast majority of research focuses on why some people have Alzheimer’s, very few are on conditions where a factor can go against this disease,” he added. By expanding understanding of what may cause the disease and exploring alternative pathways beyond amyloid plaques, researchers may uncover novel treatment options. The shared mechanisms between reelin and APOE present exciting possibilities for therapeutic interventions.
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