https://www.npr.org/sections/shots-health-news/2024/07/29/g-s1-13519/alzheimers-protein-reelin-brain-aging-amyloid-tau-memory

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A protein called Reelin may help protect brains against aging and
Alzheimer's : Shots - Health News Early in life, the protein Reelin
helps assemble the brain. Later on, it appears to protect the organ
from Alzheimer's and other threats to memory and thinking.
Shots - Health News

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A protein called Reelin keeps popping up in brains that resist aging
and Alzheimer's

July 29, 20245:00 AM ET
Jon Hamilton 2010

Jon Hamilton

Alzheimer's resilience

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A key protein called Reelin may help stave off Alzheimer's disease,
according to a growing body of research.

A key protein called Reelin may help stave off Alzheimer's disease,
according to a growing body of research. GSO Images/The Image Bank/
Getty Images hide caption

toggle caption
GSO Images/The Image Bank/Getty Images

A key protein that helps assemble the brain early in life also
appears to protect the organ from Alzheimer's and other diseases of
aging.

A trio of studies published in the past year all suggest that the
protein Reelin helps maintain thinking and memory in ailing brains,
though precisely how it does this remains uncertain. The studies also
show that when Reelin levels fall, neurons become more vulnerable.

There's growing evidence that Reelin acts as a "protective factor" in
the brain, says Li-Huei Tsai, a professor at MIT and director of the
Picower Institute for Learning and Memory.

"I think we're on to something important for Alzheimer's," Tsai says.

Various pieces of colorful trash, such as plastic bottle caps and
plastics forks, are arranged in the shape of a human brain, on a
light blue background.

Shots - Health News

The brain makes a lot of waste. Now scientists think they know where
it goes

The research has inspired efforts to develop a drug that boosts
Reelin or helps it function better, as a way to stave off cognitive
decline.

"You don't have to be a genius to be like, 'More Reelin, that's the
solution,'" says Dr. Joseph Arboleda-Velasquez of Harvard Medical
School and Massachusetts Eye and Ear. "And now we have the tools to
do that."

From Colombia, a very special brain

Reelin became something of a scientific celebrity in 2023, thanks to
a study of a Colombian man who should have developed Alzheimer's in
middle age but didn't.

The man, who worked as a mechanic, was part of a large family that
carries a very rare gene variant known as Paisa, a reference to the
area around Medellin where it was discovered. Family members who
inherit this variant are all but certain to develop Alzheimer's in
middle age.

This PET image shows the brain of a Colombian man whose memory and
thinking remained intact in his late 60s, even though he carried a
rare gene variant that nearly always causes Alzheimer's in a person's
40s.

This PET image shows the brain of a Colombian man whose memory and
thinking remained intact in his late 60s, even though he carried a
rare gene variant that nearly always causes Alzheimer's in a person's
40s. Yakeel T. Quiroz-Gaviria and Justin Sanchez/Massachusetts
General Hospital hide caption

toggle caption
Yakeel T. Quiroz-Gaviria and Justin Sanchez/Massachusetts General
Hospital

"They start with cognitive decline in their 40s, and they develop
full-blown dementia [in their] late 40s or early 50s,"
Arboleda-Velasquez says.

But this man, despite having the variant, remained cognitively intact
into his late 60s and wasn't diagnosed with dementia until he was in
his 70s.

After he died at 74, an autopsy revealed that the man's brain was
riddled with sticky amyloid plaques, a hallmark of Alzheimer's.

Scientists also found another sign of Alzheimer's -- tangled fibers
called tau, which can impair neurons. But oddly, these tangles were
mostly absent in a brain region called the entorhinal cortex, which
is involved in memory.

Want to understand your adolescent? Get to know their brain

Shots - Health News

Want to understand your adolescent? Get to know their brain

That's important because this region is usually one of the first to
be affected by Alzheimer's, Arboleda-Velasquez says.

The researchers studied the man's genome. And they found something
that might explain why his brain had been protected.

He carried a rare variant of the gene that makes the protein Reelin.
A study in mice found that the variant enhances the protein's ability
to reduce tau tangles.

Although the research focused on a single person, it reverberated
through the world of brain science and even got the attention of the
(then) acting director of the National Institutes of Health, Lawrence
Tabak.

"Sometimes careful study of even just one truly remarkable person can
lead the way to fascinating discoveries with far-reaching
implications," Tabak wrote in his blog post about the discovery.

Reelin gets real

After the study of the Colombia man was published, lots of
researchers "started to get excited about Reelin," Tsai says.

Tsai's team, though, had already been studying the protein's role in
Alzheimer's.

In September of 2023, the team published an analysis of the brains of
427 people. It found that those who maintained higher cognitive
function as they aged tended to have more of a kind of neuron that
produces Reelin.

In July of 2024, the group published a study in the journal Nature 
that provided more support for the Reelin hypothesis.

The study included a highly detailed analysis of post-mortem brains
from 48 people. Twenty-six brains came from people who had shown
symptoms of Alzheimer's. The rest came from people who appeared to
have normal thinking and memory when they died.

Interestingly, a few of these apparently unaffected people had brains
that were full of amyloid plaques.

"We wanted to know, 'What's so special about those individuals?'"
Tsai says.

So the team did a genetic analysis of the neurons in six different
brain regions. They found several differences, including a surprising
one in the entorhinal cortex, the same region that appeared to be
protected against tau tangles in the man from Colombia.

"The neurons that are most vulnerable to Alzheimer's
neurodegeneration in the entorhinal cortex, they share one feature,"
Tsai says: "They highly express Reelin."

With early Alzheimer's in the family, these sisters decided to test
for the gene

Shots - Health News

With early Alzheimer's in the family, these sisters decided to test
for the gene

In other words, Alzheimer's appears to be selectively damaging the
neurons that make Reelin, the protein needed to protect the brain
from disease. As a result, Reelin levels decline and the brain
becomes more vulnerable.

The finding dovetails with what scientists learned from the Colombian
man whose brain defied Alzheimer's. He had carried a variant of the
RELN gene that seemed to make the protein more potent. So that might
have offset any Reelin deficiency caused by Alzheimer's.

At the very least, the study "confirms the importance of Reelin,"
Arboleda-Velasques says, "which, I have to say, had been overlooked."

A breakthrough made thanks to a Colombian family

The Reelin story might never have emerged without the cooperation of
about 1,500 members of an extended Colombian family that carries the
Paisa gene variant.

The first members of that family were identified in the 1980s byDr.
Francisco Lopera Restrepo, head of the University of Antioquia's
Clinical Neurology Department. Since then, members have taken part in
a range of studies, including trials of experimental Alzheimer's
drugs.

Along the way, scientists have identified a handful of family members
who inherited the Paisa gene variant but have remained cognitively
healthy well beyond the age when dementia usually sets in.

Some appear to be protected by an extremely rare version of the APOE
gene called the Christchurch variant. Now scientists know that others
seem to be protected by the gene responsible for Reelin.

Both of those discoveries were possible because some members of the
Colombian family have been examined repeatedly in their own country,
and even flown to Boston for brain scans and other advanced tests.

"These people agreed to participate in research, get their blood
drawn, and donate their brain after death," Arboleda-Velasquez says.
"And they changed the world."

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