Decades-long Resistance to Alzheimer’s Achieved through a Rare Mutation

A man with an inherited form of Alzheimer’s was protected from developing the disease for decades thanks to a rare genetic mutation. This mutation, which had not been seen before, is the second of its kind to be discovered, following the report of a woman with a different mutation in 2019. Scientists have found that both mutations may have stopped the disease from developing for years by acting similarly in the brain. This insight could lead to new treatments for all forms of Alzheimer’s. However, some researchers are cautious about drawing conclusions from just two cases. Neurologist Rudolph Tanzi of Harvard Medical School advises that “it would be useful to see replication in more samples”.

Both individuals were members of a Colombian family with a mutation in the PSEN1 gene that causes the rare inherited variety of Alzheimer’s. People with “familial” Alzheimer’s typically display symptoms in their 40s, whereas the more common “sporadic” form does not cause symptoms until later in life. The woman with the Christchurch variant of the mutation, which is closely linked to Alzheimer’s, stayed sharp into her 70s, while the man described in the new study was still mentally healthy at 67, despite being protected years prior when he should have developed the disease earlier. Diego Sepulveda-Falla, a neurologist at the University Medical Center Hamburg-Eppendorf in Germany explains that this means “they were protected, because they should have gotten the disease 30 years earlier, and they didn’t.”

The researchers found that amyloid plaques, which many experts believe are deeply involved in Alzheimer’s, were present in both patients’ brains. However, the woman had low levels of tau tangles, clusters of proteins which are another possible Alzheimer’s culprit. These tangles, more than amyloid plaques, are thought to be closely linked to symptoms. The researchers believe that this is what spared her from dementia for decades. In the Colombian man’s brain, the researchers found that tau was severely affected and that this was due to differences in where the two protective genes were active in the brain. RELN is active in only a few places, including the entorhinal cortex, an area important for memory and one of the earliest areas affected in Alzheimer’s. Meanwhile, APOE is active everywhere. Researchers believe that the proteins produced by both mutations attach to the same molecules on cells in order to reduce the formation of tau tangles. Therefore, treating this mechanism could be the key to staving off all types of Alzheimer’s.