Rare gene mutation delays onset of early Alzheimer’s by 30 years

A brother and sister in Medellin, Colombia benefitted from a rare gene mutation that protected them from developing the early onset Alzheimer’s disease that is rampant in their extended family. How did this gene stave off symptoms for so long? And how is it related to the case of a distant relative, discovered four years ago, whose cognitive decline was delayed 30 years by a different gene mutation?

Happy senior man cropped

By Alzheimer's Prevention Bulletin

In 2020, we shared the remarkable story of a woman thought to be destined to develop Alzheimer’s disease in her 40’s because she had mutation on the presenilin 1 gene. She did not exhibit cognitive decline until her 70’s due to a rare mutation on a different gene. Now, a brother and sister from the same extended family in Colombia have also staved off the disease for years past their projected date of symptom onset.

The new discovery centers on a brother and sister who were protected from cognitive decline, with the brother having over a 20-year delay. They both carry a rare variant of Reelin, a protein that seems to provide protection from the symptoms of Alzheimer’s, with men being more protected than women. A recent study reported in Nature Medicine explained that the brother had a high level of amyloid in his brain, but far fewer tau tangles, especially around the entorhinal cortex. The sister also had protection, although not to the same extent as her brother.

The scientists who discovered this Reelin protection named the variant COLBOS in honor of the collaboration between scientists in Boston and Colombia who have been following the extended family for decades and recently identified the latest variant. This is the same team who, four years ago, discovered a woman in her 70’s from the same family with two copies of a rare, protective APOE3 mutation. She carried the presenilin 1 gene that predisposed her to early Alzheimer’s, yet stayed cognitively healthy for three decades longer than expected due to an APOE3 mutation known as Christchurch.

“Extraordinary cases like these illustrate how individuals and extended families affected by genetic mutations that cause Alzheimer’s disease can help advance our understanding of the disease and open new avenues for discovery,” said co-senior author Yakeel Quiroz, a clinical neuropsychologist and neuroimaging researcher, an associate professor of psychology, and director of the Familial Dementia Neuroimaging Lab in the Departments of Psychiatry and Neurology at Massachusetts General Hospital.

The Reelin-COLBOS or the APOE3 Christchurch variants do not seem to impact the level of amyloid in the brain. However, both cases had significantly less tau buildup.

The brother in the new case had 48 percent more amyloid plaques than typical presenilin 1 mutation carriers from this cohort, yet his tau tangles were low and reportedly sparse in the entorhinal cortex. This area of the brain usually amasses vast amounts of tau in people with this particular presenilin 1 mutation. The lack of tau seemed to spare brain neurons and protect him from cognitive impairment until later in life.

Scientists have more work ahead to explain why these three people gained so much protection from Christchurch and Reelin-COLBOS, and why men are more protected by the Reelin-COLBOS variant. Further understanding of the biochemical pathways that created these protections may be the next step in a journey toward a new avenue for the treatment and prevention of this mind-robbing disease.

“The insights we are gaining from these and other cases around the world will help guide us on where in the brain we need to look to delay and stop disease progression and will help us form new hypotheses about the series of steps that may actually lead to Alzheimer’s dementia,” Quiroz said.