MONDAY, May 15, 2023 — Researchers have discovered a genetic mutation that should actively protect people from Alzheimer’s, thanks to a man belonging to a Colombian family known to be susceptible to the degenerative brain disease.

Based on his family’s genetics, this unnamed patient should have started showing signs of Alzheimer’s in his 40s.

“They start getting impaired at age 44. By 49, they have dementia, By 60, they are dead,” said co-researcher Dr. Joseph Arboleda-Velasquez, an associate scientist at Mass Eye and Ear, a research institute with Mass General Brigham in Boston.

But this man showed no signs of cognitive decline by age 67, Arboleda-Velasquez said.

“The patient was studied and went through a battery of cognitive tests. At 67, he was fine,” he said. “He should have been dead by then, but for him, it hadn’t even started. That is just remarkable.”

The man was diagnosed with mild cognitive impairment at age 70. Imaging scans taken at 73 showed his brain was riddled with the amyloid plaques and tau tangles that are hallmarks of Alzheimer’s.

He died of pneumonia at age 74, having progressed to moderate dementia, researchers said.

Critical for protection

So what protected his brain from the ravages of Alzheimer’s?

Research conducted after his death revealed that he carried a specific mutation in a gene that regulates reelin, a protein that serves a pivotal role in brain cell development.

The mutation enhances the function of reelin, and reelin naturally hampers the process that causes tau proteins to stick together in tangles and impede brain function, Arboleda-Velasquez said.

“This mutation in reelin makes reelin work better, what we call a gain of function,” he said. “You have a situation where the mutation increases the function of a protein that already has a beneficial effect.”

Specifically, the reelin mutation appeared to have diminished the number of tau tangles that accumulated in the man’s entorhinal cortex, an area of the brain that serves a critical role in memory and learning.

“This case indicates that the entorhinal region may represent a tiny target that’s critical for protection against dementia,” senior researcher Yakeel Quiroz, director of the Familial Dementia Neuroimaging Lab at Mass General Hospital, said in a hospital news release.

The identification of this reelin gene and the brain region it most benefits should break open a new front on the war against Alzheimer’s, alongside ongoing efforts to prevent the plaques of amyloid beta protein that are another trait of the brain disease, Arboleda-Velasquez said.

“I would say 95% of the efforts for therapeutic development have focused on amyloid, and maybe 4% or 5% have focused on tau,” he said. “This shows us that there is this other pathway that doesn’t really have to do much with amyloid.”

Focus on a family

This new finding stems from ongoing research of an extended family of 6,000 people in Colombia who carry the “Paisa” mutation, a genetic variant known to significantly increase risk of early-onset Alzheimer’s.

Researchers have been following this family for three decades, and in 2019, their efforts uncovered one protective genetic mutation in a woman who remained unimpaired until her 70s.

That woman carried two copies of a variant called APOE3-Christchurch, which also appears to inhibit the development of tau tangles. The apolipoprotein E (APOE) gene is known to influence genetic risk for Alzheimer’s.

The man didn’t carry APOE3-Christchurch, so researchers went looking for another genetic factor that could explain his resilience.

The reelin mutation “would be really the second major protective factor found within this family of individuals where there’s a mutation associated with young onset Alzheimer’s disease,” said Dr. Vijay Ramanan, a neurologist with the Mayo Clinic in Rochester, Mass.

The newly discovered mutation appears to inhibit a process called phosphorylation, which induces a structural change that causes naturally occurring tau proteins to tangle with other threads of tau, Arboleda-Velasquez said. The tau tangles that occur in the brains of Alzheimer’s patients are highly phosphorylated.

Arboleda-Velasquez is confident that reelin itself could be administered as a therapy to block at least one pathway by which Alzheimer’s progresses.

“It’s very clear that the mutation offered a gain of function. If that is so, that means more reelin is better. More reelin should do it,” he said. “It’s just a matter of how we’re going to do it, how we are going to give it to patients. I think it has tremendous promise.”

Targeting tau

Ramanan, who wasn’t involved with the new research, agreed that the findings should spur research into tau as a culprit in Alzheimer’s.

“We know that there are multiple factors involved in Alzheimer’s disease. It is a complex disease and multiple pathways are contributory,” Ramanan said. “But the accumulation of tau in the brain is very tightly connected to the character of symptoms that folks experience and the timing when they experience those symptoms.”

From that standpoint alone, he said, it makes great sense to think about targeting tau as a treatment.

“When you see a genetic factor with a relationship potentially to modifying tau burden as having the ability to also protect against the development of dementia in a familial situation where there’s incredibly high risk, it really sort of adds fuel to that direction of research,” Ramanan added.

The new study was published May 15 in the journal Nature Medicine.

More information

The U.S. National Institute on Aging has more about the hallmarks of Alzheimer’s disease.

SOURCES: Joseph Arboleda-Velasquez, MD, PhD, associate scientist, Mass Eye and Ear, Boston, and associate professor, ophthalmology, Harvard Medical School, Boston; Vijay Ramanan, MD, PhD, neurologist, Mayo Clinic, Rochester, Minn.; Mass General Brigham, news release, May 15, 2023; Nature Medicine, May 15, 2023