Rare genetic mutation holds clues to preventing Alzheimer’s

Could one woman’s rare genetic mutation one day have a global impact on dementia risk? It’s possible, say investigators who report on a potentially groundbreaking case of a woman whose genetic mutation staved off dementia for decades, even though her brain had already been damaged by Alzheimer’s disease. While most Alzheimer’s cases are not driven by genetic predisposition, one woman in Colombia is among about 1,200 in her country who do face a genetically higher risk for early-onset Alzheimer’s. Why? They all carry the E280A mutation of a gene called Presenilin 1 (PSEN1), which is known to increase the chances for Alzheimer’s at a far younger age than usual.

We identified an individual that was predisposed to develop Alzheimer’s in her 40s,” noted study author Dr. Joseph Arboleda-Velasquez. He’s an assistant professor of ophthalmology with the Schepens Eye Research Institute of Mass Eye and Ear at Harvard Medical School, in Boston.

But, strangely, the woman “remained unimpaired until her 70s,” Arboleda-Velasquez added. The twist: the woman had, in fact, developed clear telltale signs of Alzheimer’s in her brain. She just hadn’t developed dementia. For example, while she had fewer neural “tangles” in her brain than is typical for Alzheimer’s patients, by the time she hit her 40s she did have the same unusually high level of brain amyloid-beta deposits as her E280A peers. Such deposits are a key signature of Alzheimer’s. So why didn’t she develop middle-aged dementia like her peers?

To unravel the mystery, Arboleda-Velasquez and his colleagues ran an in-depth genetic analysis on the woman. And what they found is that she had not just one mutation, but two. In addition to the E280A mutation, she also carried the so-calledChristchurchmutation in the APOE3 gene. But there’s more. Not only did she carry the Christchurch mutation, but she had two of them. Some of her E280A peers (about 6%) also carried a single copy of Christchurch. But she was the only one who carried two, the investigators found. “It is ultra-rare, with an approximate prevalence of less than one in every 200,000 individuals,” Arboleda-Velasquez said.

And having one such rare mutation did not appear to be enough. No protection against dementia was linked to only one Christchurch mutation. But as this woman’s case suggests, having two such mutations did seem to throw up a shield against Alzheimer’s, preserving her ability to remember things and think clearly for a few decades, long after her E280A peers had started experiencing cognitive decline.

Source: https://www.cbsnews.com/