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Researchers report that a rare genetic mutation may help delay the onset of early Alzheimer’s. Tara Moore/Getty Images
  • Researchers say a gene variant appears to have helped delay the onset of early Alzheimer’s in a second individual who carried a genetic mutation that puts people at high risk of developing the disease.
  • Most people with the genetic mutation develop Alzheimer’s before age 50 and die before age 60.
  • The man in the new study retained full cognitive functions until age 67 before developing dementia and dying at the age of 74.

People who inherit a genetic mutation called PSEN1 E280A are virtually guaranteed to develop Alzheimer’s disease by their mid-to-late 40s.

However, researchers in a new case study published in the journal Nature Medicine have concluded that a different gene variant appears to protect against early onset dementia.

Researchers say that a Colombian man who carried the PSEN1 E280A mutation but also had a rare variant of a brain protein involved in the RELN gene — retained his full cognitive functions until age 67. He eventually developed dementia and died at age 74.

Most carriers of the PSEN1 E280A mutation develop mild cognitive impairment by the median age of 44 years and dementia by 49 years.

The researchers say they found that the man’s sister, who had a similar genetic profile, also seemed to gain some protection, remaining cognitively sound until her mid-50s and didn’t develop dementia until age 61.

“People that have these genes don’t just have a risk factor. It’s causative, everyone gets it, usually in their 40s,” Dr. Joseph F. Arboleda-Velasquez, a study co-author and an associate professor of ophthalmology at Harvard Medical School in Boston, told Medical News Today. “It’s remarkable that [these individuals]… beat the odds.”

Arboleda-Velasquez was also involved in a 2019 study which found that another woman with the PSEN1 E280A mutation was seemingly protected from developing Alzheimer’s because she carried two copies of a mutated gene that inhibited the action of brain chemicals involved in spreading tau proteins.

The researchers in the new study noted that the male subject, who worked until he was 60, was married and had two children.

They say he likely gained 26 years of quality lifespan due to genetic protective factors.

Researchers also found that the subject with the protective gene variant, called RELN-COLBOS, still exhibited many of the systemic brain symptoms typical of Alzheimer’s disease, including amyloid plaques and neurofibrillary “tau” tangles.

However, these were greatly reduced in the entorhinal cortex, the region of the brain where the RELN gene — which controls production of a protein called reelin — is most active.

Arboleda-Velasquez pointed out that this also is the part of the brain where Alzheimer’s symptoms typically appear first.

“The patient had plenty of plaques and tau tangles, yet neurons didn’t die” as typically occurs in later-stage Alzheimer’s disease, he says. “The findings tell us that it’s possible to have protection against Alzheimer’s even if the patient has a lot of pathology.”

“This is a fascinating and potentially very important new finding because the protein, reelin, has been implicated in multiple processes as diverse as brain development, psychiatric illness, and Alzheimer’s. Yet, there has never been such clear and striking evidence that reelin is indeed involved in Alzheimer’s,” Dr. Dale Bredesen, a neuroscience researcher and neurodegenerative disease expert, told Medical News Today.

“Since reelin is involved in synaptic plasticity, and has overlapping signaling with other molecules involved in Alzheimer’s… the involvement of reelin in Alzheimer’s makes good sense,” he added.

Arboleda-Velasquez says the findings open up the possibility that therapeutic interventions can be designed to slow the progress by delivering RELN to the entorhinal cortex.

“A localized treatment could have a profound clinical impact,” he says.

Arboleda-Velasquez noted that the RELN protein could be synthesized in a lab and delivered in a variety of ways to the brain, perhaps as part of combination therapy with treatments designed to reduce plaques.

“Reelin signaling is complex, so this will not be simple, but there are multiple potential sites for intervention,” says Bredesen. “For example, reelin interacts with the amyloid-beta peptide … and this may impair reelin signaling; increasing the signaling may therefore be therapeutic,” he said.

Reelin also interacts with receptors like VLDLR and ApoER2 that also are known to play a role in Alzheimer’s disease, as well as the protein coding gene Dab1 that interacts with APP, the parent molecule for amyloid-beta peptide, according to Bredesen.

“All of these various signaling components may be therapeutic targets,” he said.

A RELN-focused therapy also could one day offer hope to people with advanced Alzheimer’s.

“They don’t even get amyloid plaque drugs and these people need help,” Arboleda-Velasquez said.

However, Bredesen cautioned, “It’s important to remember that this is a genetic case of Alzheimer’s and thus may or may not be relevant to the other 95 percent of Alzheimer’s.”

“Alzheimer’s disease affects the brain widely and so beginning a reelin-targeted therapeutic after symptoms begin, or after pathophysiological changes set in, may or may not halt the changes outside the entorhinal cortex,” he explained.