By
Alan Mozes November 4, 2019 / 12:33 Pm / Healthday
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-called "Christchurch" mutation 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.
"This is the first time a specific patient who carries
the [double] mutation has been linked to such a protective benefit,"
Arboleda-Velasquez noted.
How does it work? It seems that "the mutation puts a
block on the cascade of events linking amyloid accumulation to neural [brain
cell] death," he explained.
The team did acknowledge that more research will be needed
to definitively confirm the Christchurch mutation's impact, and to further
explore how this mutation/dementia delay connection truly works.
But, in theory, the incredibly rare experience of this one
woman in Colombia could ultimately have profound ramifications for Alzheimer's
patients around the world, if "new drugs that mimic the effect of [the]
mutation" could be developed, said Arboleda-Velasquez. Rather than
stopping Alzheimer's from developing, such drugs would prevent Alzheimer's from
causing dementia.
The study was published Nov. 4 in the journal Nature
Medicine, and was partly funded by the U.S. National Institutes of Health
and the Alzheimer's Association.
Heather Snyder, vice president of medical and scientific
relations at the Alzheimer's Association, characterized the findings as
"an important discovery."
The insights gleaned from a look at this particular
patient's experience are "full of possibilities for increasing our
understanding of Alzheimer's disease and all dementia, and
advancing potential avenues for treatment," Snyder suggested.
"Understanding what is happening in the brains of
people when there appears to be a delay or stopping of the disease progression
— because of this gene form or otherwise — gives rise to many possibilities for
investigating new treatment and risk-reduction opportunities," she added.
At the same time, Snyder cautioned that "more research
is needed to understand more thoroughly how genetics impacts
Alzheimer's/dementia risk, and to expand and confirm these findings in a larger
number of people."
First published on November 4, 2019 / 12:33 PM
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