2023-05-15 17:01:44
A study that is published this Monday in the journal «Nature Medicine» provides information about pWhy some people can be more resistant to Alzheimer’s disease than others. Some people who carry mutations in genes known to cause early-onset Alzheimer’s disease do not show signs of the condition until very late in life, much later than expected. The findings may lead to strategies to delay or prevent the condition.
The identified mutation increases the function of the Reelin protein and thereby promotes the survival of neurons. It is a recently rare genetic variant identified from the RELN gene (encoding the reelin signaling protein) and which according to him is associated with more than two decades of resistance to autosomal dominant Alzheimer’s disease (ADAD).
This is the second case of such resilience from a large family of more than 6,000 living members from Colombia, who did not develop mild cognitive problems nearly two decades after the typical age of onset. “The research discovers a new molecular pathway that could be a therapeutic target to potentially increase resilience in all forms of Alzheimer’s disease,” explains Joseph F. Arboleda-Velásquez, from ABC Salud. Harvard Medical School (USA) and one of the authors of this work.
ADAD is a rare inherited form of Alzheimer’s disease, which is most commonly caused by specific mutations in the PSEN1 gene encoding the transmembrane protein presenilin 1. It is characterized by the early onset of cognitive impairment, such as memory deficits, at a early age, typically 40-50 years of age.
The previous case involved a woman who carried the E280A mutation in a gene called Presenilin 1 (PSEN1), which has been shown to cause early-onset Alzheimer’s disease.
It also had two copies of a genetic variation called ChristChurch, named for the New Zealand town where it was first found in the APOE3 gene (APOE3ch). Said woman remained no cognitive problems for almost 30 years after the expected age of onset, even though it also showed evidence of Alzheimer’s disease in the brain.
What the team led by Francisco Lopera, Yakeel T. Quiroz, Joseph F. Arboleda-Velásquez and Diego Sepúlveda-Falla has done is to analyze the clinical and genetic data of 1,200 people in Colombia who carry the PSEN1 mutation and are predisposed to ADAD.
Thus, they identified a man who remained cognitively intact until age 67 despite having the PSEN1 mutation for early-onset ADAD.
The authors compared this person to the case of the woman with ADAD. Both people showed widespread and considerable amyloid pathology in the brain, which is a pathological hallmark of Alzheimer’s disease.
However, explains to ABC Salud Diego Sepúlveda-Falla, from the University Medical Center Hamburg-Eppendorf, (Germany), “There was limited aggregation of tau (a microtubule stabilizing protein in the brain) in the entorhinal cortex, a region of the brain that is characteristically affected in the early clinical stages of Alzheimer’s disease.”
The authors performed the genetic sequencing and found that this second person harbored a different type of mutation: a new rare variant of RELN (H3447R called COLBOS).
Sepúlveda-Falla explains that this mutation “causes a RELN ligand, a binding molecule, which may be more effective in limiting tau aggregation, but more research is needed to explore this.”
The APOE and reelin proteins involved in the protection of these individuals function as ligands for common cellular receptors, and the authors indicate that this could suggest a common mechanism for the Alzheimer’s resistance.
The findings highlight a previously unknown molecular pathway that may confer resilience to cognitive decline in people at increased risk of Alzheimer’s disease.
“There is currently a great need for more effective therapies against Alzheimer’s and this discovery indicates a new therapeutic target that can protect for several decades,” Arboleda-Velásquez told ABC Salud.
Studying these individuals may reveal new information about genetic variants that reduce the risk of developing Alzheimer’s disease and other forms of dementia, the researchers conclude.
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