A newly identified rare genetic variant of the RELN gene (encoding the signaling protein reelin) identified by German scientists in a man has been linked to the resilience of autosomal dominant Alzheimer’s disease (ADAD) for more than 20 years. This is the second case report of such resilience, highlighting a new molecular pathway, which may be a therapeutic target, to potentially increase resilience in all forms of Alzheimer’s disease. The study was published May 15 in Nature Medicine.
ADAD is a rare inherited form of Alzheimer’s disease, most commonly caused by a specific mutation in the PSEN1 gene, which encodes the transmembrane transporter Progerin 1. It is characterized by early-onset cognitive impairment, such as memory loss at a young age (usually between the ages of 40 and 50). A previously reported case described a woman with ADAD with a rare mutation called “Christchurch,” in the gene encoding apolipoprotein E (APOE), who remained cognitively accessible for nearly 30 years after her expected age of onset, despite showing signs of Alzheimer’s in her brain.
Francisco Lopera, Yakeel T. Quiroz, Joseph F. Arboleda-Velasquez, Diego Sepulveda-Falla and colleagues at the Hamburg-Eppendorf University Medical Center analyzed clinical and genetic data from 1,200 people with PSEN1 variants and predisposition to ADAD from Colombia. They found that a man who carried the PSEN1 variant of early-onset ADAD remained cognitively intact until age 67. The authors compared this man to women who had previously reported ADAD delay. Widespread and massive amyloid pathology appeared in both brains, which is a pathological feature of Alzheimer’s disease. However, tau (a microtubule-stabilized protein in the brain) has limited accumulation in the entorhinal cortex, a brain region typically affected by the early clinical stages of Alzheimer’s disease. The authors performed genetic sequencing and found that the second patient had a different type of variant: a rare new variant of RELN (H3447R, called COLBOS). The authors suggest that this variation leads to a RELN ligand, a binding molecule, which may be more effective at limiting tau protein accumulation, but further research is needed to explore this. The APOE and reelin proteins, which are involved in protecting these people, function as ligands for general cell receptors, which the authors say could imply tolerance to common mechanisms for Alzheimer’s.
The researchers say the findings highlight a previously unknown molecular pathway that may confer resilience to cognitive impairment in people at increased risk of Alzheimer’s. (Source: Feng Weiwei, China Science News)
Image courtesy of Pixabay
Related paper information:https://doi.org/10.1038/s41591-023-02318-3
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