SA new study looks at biomarkers that
may help detect Alzheimer’s sooner.
- The presence of neurofibrillary
tangles in the brain is one of the key hallmarks of Alzheimer’s disease.
- These irregular clumps of protein
are closely associated with disease progression.
- Scientists have now designed a way
to detect the very early stages of their development.
- They
hope this discovery will pave the way for earlier diagnosis and,
therefore, better response to treatment.
Scientists know that a build-up of
specific proteins in the brain is associated with Alzheimer’s disease.
However, by the time these proteins
have become visible in brain scans, disease progression is well underway,
meaning that medications are less effective.
A new study, which appears in Nature MedicineTrusted Source, has identified a biomarker that may
eventually allow doctors to spot the early signs of protein buildup before it
causes significant damage.
“Detecting Alzheimer’s disease before
irreversible neurodegeneration could improve the efficacy of available
treatments,” Jennifer
Bramen, PhD told Medical
News Today.
Bramen, who was not involved in the
study, is a senior research scientist and director of neuroimaging at the
Pacific Neuroscience Institute at Providence Saint John’s Health Center in
Santa Monica, CA.
Alzheimer’s protein hallmarks: What are they?
Two main protein structures are
associated with Alzheimer’s disease: amyloid-beta
plaquesTrusted Source and neurofibrillary tangles
(NFTs).
1. Amyloid-beta: As Alzheimer’s disease develops,
amyloid precursor proteins clump together to create amyloid-beta plaques, which
eventually disrupt how brain cells work.
2. Tau: In the healthy brain, tau helps
maintain the structure of neurons. In the brain of someone with Alzheimer’s
disease, this protein goes awry and develops into NFTs.
Tau can become phosphorylated,
meaning that phosphate groups are added to it. This is normal, but in the case
of Alzheimer’s, the phosphorylation is abnormal or excessive.
Tau with abnormal phosphorylation is
referred to as hyperphosphorylated, and it clumps together to form
NFTs, which gradually build up inside cells, causing their death.
Studies show that increased levels of
hyperphosphorylated tau are associated with worse cognitive symptoms of
Alzheimer’s.
Because amyloid-beta tends to arrive
on the scene earlier than NFTs, most attempts to look for early biomarkers have
focused there. However, “a large percentage of people who have brain
amyloid-beta deposits will never develop dementia,” explains the study’s senior author,
Thomas Karikari, Ph.D.
In other words, it does not make an
effective biomarker.
In contrast, levels of NFTs in the
brain correlate better withTrusted Source disease progression. “Once the
tau tangles light up on a brain scan,” explains Karikari, “it may be too late
to put out the fire and their cognitive health can quickly deteriorate.”
For these reasons, in the hunt for a
new biomarker, the researchers focused on spotting early signs of NFT
development.
It takes tau to tangle
The scientists focused on the
“building blocks” of NFTs, including oligomers and protomers, which they refer
to collectively as soluble tau assemblies.
Very little is known about the nature
of these compounds and how they function. However, they do know that the early
phase of NFTs’ development is more toxic to brain cells than the fully formed
NFTs.
In their multipronged study, the
researchers first successfully measured soluble tau assemblies in brain samples
from people who died with Alzheimer’s. Then, they identified a pivotal stage of
NFT development and phosphorylation sites that seem important for forming NFTs.
They showed that the presence of
these phosphorylation sites, called p-tau-262 and p-tau-356, could predict
future NFT production, making them potential biomarkers for early disease.
MNT spoke with Adrian M. Owen, PhD, chief scientific officer at Creyos, and a professor of
cognitive neuroscience and imaging at the University of Western Ontario,
Canada, who was not involved in the study. He explained that the scientists
also “demonstrated that these early tau aggregates disrupt neuronal function in
mouse brain tissue, suggesting their role in cognitive decline.”
“Our test identifies very early
stages of tau tangle formation — up to a decade before any tau clumps can show
up on a brain scan,” explains senior author Thomas Karikari,
Ph.D.
The importance of catching Alzheimer’s early
MNT contacted Dr. Chris Vercammen,
a board certified internal medicine physician and medical director at Remo Health who was not involved in the study. We asked about the
value of detecting Alzheimer’s during its early phase.
“It allows doctors to start
treatments and make helpful lifestyle changes sooner, which can help slow the
disease’s progress, even though we can’t currently cure it.”
Owen outlined two additional
important reasons why early detection is so important.
Firstly, early detection can help
people plan their life. For the same reason, Owen explained, “it is equally
important to accurately detect when someone is not likely to
develop dementia.”
Expanding on this final point, Owen
told MNT, “It can bring tremendous peace of mind — and assist
with making end-of-life plans — to know that you are unlikely to be on the road
to a dementing illness.”
However, Vercammen noted an important
limitation of the study: “While this study offers some interesting results,” he
told MNT,
“it’s important to remember that the testing methods used here were based on
autopsies that examined brain tissues from people who had been diagnosed with
Alzheimer’s disease after their deaths.”
“So, the implications for treatments
that could be used at scale in people living with the disease are still quite a
way off.”
Ethical concerns and the trouble with biomarkers
While discovering a way to detect
Alzheimer’s early would be an exciting step forward in the treatment of such a
challenging and devastating condition, Vercammen brings up some important
ethical questions.
“How will this diagnostic information
be used? Will it dictate treatment decisions, eligibility for clinical trials,
or even insurance coverage?” he asked.
He worries that a positive test result in
someone without symptoms is “particularly concerning” as it would cause
“significant anxiety and distress for both them and their family.”
“In my opinion,” he continued, “any
future diagnostic test derived from biomarkers must include robust counseling
and education to ensure people understand the test’s limitations and the
implications of a positive result.”
Along similar lines, Owen told MNT that
it’s important to differentiate between a biomarker and a risk factor. He
explained that, regardless of the biomarkers you might have, if you do not
exhibit all the symptoms of dementia, you will not be diagnosed as such.
“This is important because many
people assume that expensive, invasive, and time-consuming blood tests, brain
scans, or other so-called ‘biomarkers’ are necessary and important for
diagnosing dementia,” he said.
“Usually,” Owen continued, “these
just reveal correlates of the dementing process rather than prove that someone
has dementia.”
These tests will not correctly
identify all people who will go on to develop dementia and may predict some
will develop dementia when they do not.
Overall, despite the many caveats,
this study is a step forward in our understanding of Alzheimer’s. However, only
time and much more research will tell whether it truly catches the condition
early in the clinic.