Study: Rare genetic mutation appears to have protected second person from early Alzheimer’s

For the second time in one extended family, researchers have identified a person who seemed genetically destined to develop early Alzheimer’s, but remained cognitively sound for several more decades.

Like with the first case, the scientists zeroed in on another genetic variant that seemed to be protective, overcoming the impact of the mutation that would have otherwise set this man on the course for dementia in his 40s. Notably, it was in a different gene than in the first case, signaling there are multiple pathways that appear to stave off cognitive decline.

The man only started showing cognitive impairment at 67, and progressed to dementia at 72. He died at 74.


“It seems that it is possible to have decades-long protection against Alzheimer’s disease,” said Joseph Arboleda-Velasquez, a cell biologist at Mass Eye and Ear and one of the authors of the new study, published Monday in Nature Medicine.

Arboleda-Velasquez is part of a team of scientists who for years have been studying a large extended Colombian family, some 1,200 of whom have a mutation in a gene called PSEN1 that causes the production of the protein fragment beta-amyloid to go into overdrive. Plaques of amyloid crowd around neurons and, many researchers believe, in part fuel the cognitive decline associated with Alzheimer’s. Many family members who have the mutation experience cognitive impairment by age 44 and dementia by 49.


But in 2019, the researchers described the case of a woman with the PSEN1 mutation who was cognitively healthy until her 70s, despite, as imaging showed, having a brain full of amyloid. After sequencing her genome, they found that she had inherited two copies of a very rare form of the gene APOE3, known as the Christchurch mutation. Lab experiments indicated that the mutated form of the APOE3 molecule dampened the spread of tau, also a protein fragment and hallmark of Alzheimer’s but one that builds up inside and kills neurons. Brain imaging showed the woman had comparatively low levels of tau accumulation.

After that discovery, the research team wondered if more people were protected from developing Alzheimer’s. There are so many family members participating in the study that it’s enabled researchers to pick up patterns and detect outliers as well.

“You collect more patients and more patients, you start to see that some patients do not develop dementia for another 10 years, 20 years, 30 years, and you think something’s going on here,” said Diego Sepulveda-Falla, an author of the new report who studies the neuropathology of Alzheimer’s at University Medical Center Hamburg-Eppendorf in Germany.

When the researchers identified the man described in the new paper, their initial hypothesis was that he too had two copies of the Christchurch mutation. Sequencing, however, showed that wasn’t the case. Moreover, imaging showed he had high levels of tau as well as amyloid in his brain, though the tau wasn’t everywhere. In particular, he had little tau in an area called the entorhinal cortex, which is involved in cognition and learning, compared to other family members who did develop dementia earlier in life.

After hunting through his DNA, the researchers settled on another genetic variant that appeared to safeguard the man, a form of a gene called RELN, or reelin. The RELN molecule plays a crucial role in development, directing neurons where they need to go and helping form synapses. It also seems to help slow the buildup of tau in neurons. In the man’s case, the one copy of the mutated form he had seemed to boost the activity of the molecule, helping limit disease-causing tau, at least in parts of the brain.

The findings suggest that “the preservation of the entorhinal cortex is very important for extreme protection against Alzheimer’s,” Yakeel Quiroz, the director of Massachusetts General Hospital’s Familial Dementia Neuroimaging Lab and one of the authors of both the 2019 and new papers, wrote in an email.

The researchers named the mutation RELN-COLBOS, a reference to the name of the broader Mass General Colombia-Boston biomarker study that the case report is a part of.

Outside scientists have praised the research that the Colombian family has enabled, but with both the new and the 2019 report, some have questioned whether one genetic variant can truly be responsible for sparing someone from developing Alzheimer’s for decades. All of us have thousands of tiny genetic tweaks, so some experts think it would be difficult to say definitively that the RELN-COLBOS variant was the precise reason the man in the study seemed to be protected. The rarity of these cases make the findings harder to prove.

“It’s very difficult to be sure which variant, or variants, endowed our brains with that resilience,” said Nikolaos Robakis of the Icahn School of Medicine at Mount Sinai, who has studied the genetic variants for early-onset Alzheimer’s and was not involved in the new study. “We’ll have to do lots of work on that.”

Arboleda-Velasquez acknowledged other mechanisms could be involved in the resilience experienced by this man, and in the paper, the scientists list other variants the man had that are of potential interest. But the research team also thinks there is therapeutic potential in what they’ve discovered. If antibodies or other molecules could be developed that mimic the effect of these mutations on the accumulation of tau, for example, that could provide a medicinal form of the protection that these individuals had in their genes.

The researchers have already been at work turning their research with the Christchurch mutation into potential therapeutic antibodies, and Arboleda-Velasquez has also co-founded a company called Epoch Biotech to pursue “resilient case-inspired therapeutics.” The researchers said they now plan to do the same with what they’ve learned about the RELN mutation.

Source: STAT