How a genetic mutation protected a patient from Alzheimer's

For several decades, researchers have been following roughly 6,000 members of an extended family in Colombia who are predisposed to develop Alzheimer's at an early age. Many members have a genetic variant called the paisa mutation, which almost always leads to early-onset dementia.

Individuals who carry this mutation typically develop mild cognitive impairment at the median age of 44, which then evolves into dementia at age 49. Many will die from complications of dementia by their 60s.

However, researchers have also identified some carriers who have been able to stay cognitively unimpaired until much older ages. For example, in 2019, researchers described the case of a woman with the paisa mutation who didn't experience cognitive impairment until her 70s.

In her case, the woman had also inherited a rare mutation to the APOE3 gene, which was called the Christchurch mutation. According to lab experiments, this mutation decreased the spread and accumulation of tau, a protein that can build up and destroy neurons.

Since then, researchers have identified another member of the family with a genetic mutation that may have protected them from developing early-onset Alzheimer's. In this new case, a man with the paisa mutation did not develop cognitive impairment until age 67, which then progressed to mild dementia at age 72. He ultimately passed away at age 74, many years after most people with the same paisa mutation do.

Although scans of the patient's brain showed high levels of amyloid plaques and tau, both of which are thought to be common markers of dementia, his entorhinal cortex, which helps coordinate memory and navigation, had low tau levels.

Initially, researchers believed that the man had the same Christchurch mutation as the previous patient, but this was not the case. Instead, they discovered that he had a mutation in the gene that codes for reelin, a protein that is crucial in regulating brain cell development and function.

Usually, mutations to the reelin gene are associated with brain disorders, such as autism and schizophrenia, but in this patient's case, the mutation seemed to be protective. In animal experiments, researchers found that the mutation seemed to limit tau accumulation around neurons in genetically engineered mice.

According to Yakeel Quiroz, director of the Familial Dementia Neuroimaging Lab at Massachusetts General Hospital and one of the study's authors, the findings suggest that "the preservation of the entorhinal cortex is very important for extreme protection against Alzheimer's."

What does this finding mean for Alzheimer's research?

The two protective cases that have been identified "are forcing us to revise our previous concepts about neurodegeneration and cognitive decline," said Diego Sepulveda-Falla, a principal investigator at the Institute of Neuropathology at the University Medical Center Hamburg-Eppendorf. "These are exciting times for us, and hopefully for the Alzheimer's research field as well."

According to Joseph Arboleda-Velaquez, a cell biologist at Massachusetts Eye and Ear and a member of the research team, the study's findings "really [hold] the secret to the next generation of therapeutics." If an antibody or another molecule could mimic the effect of protective mutations, patients could have a targeted treatment against tau accumulation and subsequent dementia.

Currently, the researchers are working to identify additional patients with protective genes from the Colombian families and to develop treatments that potentially target the different protective pathways for dementia.

"These are the kinds of insights we cannot gain without patients," Arboleda-Velaquez said. "They are showing us what's important when it comes to protection, and challenging many of the field's assumptions about Alzheimer’s disease and its progression." (Bridger, Harvard Gazette, 5/15; Kolata, New York Times, 5/15; Joseph, STAT, 5/15; Reardon, Nature, 5/15)

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