Colombian man found to have genetic resilience to Alzheimer's

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Medicine: Rare genetic resilience to Alzheimer’s disease identified in a second patient

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A newly identified, rare genetic variant of the gene RELN (which encodes the signaling protein reelin) is associated with over two decades of resilience to autosomal dominant Alzheimer’s disease (ADAD) in a male individual, according to a new study published in Nature Medicine. This is the second case of such resilience reported and highlights a novel molecular pathway that could be targeted therapeutically to potentially increase resilience across all forms of Alzheimer’s disease.

ADAD is a rare inherited form of Alzheimer’s disease, which is most commonly caused by specific mutations in the gene PSEN1 that encodes the transmembrane protein presenilin 1. It is characterized by early onset of cognitive impairment, such as memory deficits, at a young age, typically at 40–50 years of age. A previously reported case detailed a woman with ADAD who had a rare variant, called Christchurch, of the gene encoding apolipoprotein E (APOE) and remained cognitively unimpaired for nearly 30 years after the expected age of onset, despite also showing evidence of Alzheimer’s disease in the brain.

Francisco Lopera, Yakeel T. Quiroz, Joseph F. Arboleda-Velasquez, Diego Sepulveda-Falla and colleagues analyzed clinical and genetic data from 1,200 people from Colombia who carry the PSEN1 mutation and are predisposed to ADAD. They identified a man who remained cognitively intact until 67 years of age despite carrying the PSEN1 mutation for early onset ADAD. The authors compared this person with the woman with previously reported delayed ADAD. Both people showed widespread and considerable amyloid pathology in the brain, which is a pathological hallmark of Alzheimer’s disease. However, there was limited aggregation of tau (a microtubule-stabilizing protein in the brain) in the entorhinal cortex, a brain region that is characteristically affected in the early clinical stages of Alzheimer’s disease. The authors conducted genetic sequencing and found this second person harboured a different type of mutation: a novel rare variant of RELN (H3447R termed COLBOS). The authors suggest that this mutation results in a RELN ligand, a binding molecule, that may be more effective at limiting the aggregation of tau, but more research is needed to explore this. The APOE and reelin proteins involved in the protection of these individuals function as ligands of common cell receptors and the authors indicate this could suggest a common mechanism for resilience to Alzheimer’s.

The authors conclude that their findings highlight a previously unknown molecular pathway that may confer resilience to cognitive impairment in people at increased risk for Alzheimer’s disease.