Animal research may be bringing us a step closer to new treatments for those genetically predisposed to Alzheimer’s disease.
- Alzheimer’s disease is
the commonest form of dementia, causing up to 70% of the 55 million
dementia cases worldwide.
- Around half of those
who develop Alzheimer’s disease have a variant of one gene — APOEe4— that increases the risk of developing the condition.
- This gene variant
prevents cells clearing the beta-amyloid plaques that are characteristic
of Alzheimer’s disease.
- Now, a study in
nematodes and mice has identified a molecule that can inhibit APOEe4 and allow the cells to clear these beta-amyloid deposits, and
potentially alleviate Alzheimer’s disease symptoms.
With an aging global population,
dementia is a growing concern worldwide. A recent forecast by The Lancet estimated that the
worldwide burden of dementia is set to almost triple by 2050.
Of these dementia cases, according to
the World Health Organization (WHO), 60–70% are due to Alzheimer’s
disease.
For dementia, the greatest risk
factor is aging — with the likelihood of developing dementia increasing each
year from the age of 65.
Genetics can also influence whether a
person develops dementia: About 1% of cases of Alzheimer’s disease are entirely caused by
genes, and other genes increase the risk of developing Alzheimer’s.
The gene that expresses apolipoprotein
E, the APOE gene, influences Alzheimer’s disease
risk. One variant, or allele, of this gene, APOEe4, increases the risk
of Alzheimer’s disease, with between 40–65% of people with Alzheimer’s disease
having at least one copy of this allele.
Dr. Emer MacSweeney, CEO and medical director at Re:Cognition
Health, told Medical News Today:
“In 2018,
it was shown those with an APOEe4 gene are less able to
clear waste products from the brain and, therefore, more susceptible to
building up toxic levels of amyloid and tau protein, which is the hallmark of
Alzheimer’s disease. The toxic amyloid and tau protein relentlessly destroy
further brain cells, with the progression of the characteristic symptoms of
[Alzheimer’s disease].”
Now, a team led by researchers at the
University of Arkansas for Medical Sciences have found a molecule that binds
to APOEe4and inhibits its harmful effects. They suggest it may
form the basis for a new treatment for Alzheimer’s disease with a genetic
basis.
The research is published in Communications Biology.
Dr. MacSweeney, who was not involved
in the research, welcomed the study.
She said: “This study focuses on the
role of the APOE gene, specifically the APOEe4 allele,
in Alzheimer’s disease and explores a potential therapeutic strategy using
small molecules to target APOEe4. The research combines genetic
association studies, cellular mechanism investigations, computational
modelling, and experimental validation.”
APOEe4 gene variant linked to amyloid plaques
Studies have shown that APOEe4 has
several effects, including disrupting
lipid metabolism and driving
beta-amyloid pathology. Both of these can increase the risk of
dementia, but for Alzheimer’s disease, beta-amyloid pathology is key.
This latest study found that APOEe4 blocks
genes responsible for autophagy —
the breakdown and recycling of worn out cell parts and macromolecules in cells.
If these genes are inhibited, molecules such as beta-amyloid build up rather
than being recycled.
When beta-amyloid builds up it forms
plaques on and around nerve cells, which is thought to drive the cognitive
impairment and other symptoms that are characteristic of Alzheimer’s disease.
The researchers used in vitro and
in vivo models in both Caenorhabditis
elegans — a nematode worm widely used in genetic research
— and mice.
In molecular models, they first
identified the site on DNA where APOEe4 binds to inhibit
autophagy. They then investigated molecules that could block this region to
prevent APOEe4 binding, allowing autophagy of beta-amyloid
to continue.
One molecule — CBA2 — bound to a
stable “pocket“ region on APOEe4, blocking its activity.
Dr. Heather M. Snyder, Ph.D., Alzheimer’s Association vice
president of Medical and Scientific Relations, not involved in this study,
commented on its findings, noting that:
“It is
exciting to see advances in technology that may accelerate therapy discovery.
And it is exciting that this newly announced research is looking at a novel and
understudied therapeutic target — APOEe4 and its actions in
the brain. But the research is very preliminary; it is being conducted in mouse
and other animal models of Alzheimer’s. We are still far from knowing whether
this experimental treatment will be safe and effective in people.”
Molecule
inhibits APOEe4 to prevent amyloid build-up
Once the molecule bound to the stable
region, it inhibited the gene, as Dr. MacSweeney explained to MNT:
“The lead compound, CBA2, is found to selectively bind to this pocket,
demonstrating efficacy in restoring autophagic transcription in APOEe4-expressing
models, including primary astrocyte cultures and T98G cells.”
In C. elegans nematodes
genetically altered to show Alzheimer’s disease-like changes, CBA2
significantly reduced the build up of beta-amyloid, and reversed the decline
in chemotaxis,
the worms’ response to a chemical stimulus.
When researchers treated the mice
modified to express APOEe4, expression of the autophagy genes
increased. Dr. MacSweeney told MNT that the results were encouraging, but urged
caution.
“In mice with APOEe4,
CBA2 boosts the activity of key genes linked to cleaning up harmful substances
in the brain, an important part of Alzheimer’s. However, the effects are
stronger in mice with APOEe4 than in those with APOEe4,”
she explained.
“While these findings are positive,
more research and testing in humans are needed to confirm CBA2’s potential
benefits for Alzheimer’s,” she added.
Potential
new treatment target for those genetically at risk
The researchers suggest that CBA2
might form the basis of treatment to help avoid amyloid build up in people with
the gene.
“CBA2, identified as a promising therapeutic compound, demonstrated effectiveness in mitigating APOEe4-associated issues in both worms and mice. If proven safe and effective in humans, CBA2 could represent a targeted treatment to address molecular and behavioural aspects of [Alzheimer’s disease], particularly for individuals carrying the APOEe4 allele.”– Dr. Emer MacSweeney
Dr. MacSweeney welcomed the findings,
saying that “[t]his is the first time a potential compound to specifically
block the harmful effects of APOEe4 has been described.”
“These results suggest hope,
particularly for the 25% of the population who inherit one copy of the APOEe4 gene
and are three times more likely to develop [Alzheimer’s disease] between ages
65-85, than an individual who does not have an APOEe4 gene.
And the 2-3% of the population who inherit two APOEe4 genes;
these individuals are 12-15 times more likely to develop [Alzheimer’s disease]
than the general population,” she told us.
This optimism was echoed by Dr.
Snyder, who suggested that targeting APOEe4 might form part
of a multifaceted approach to Alzheimer’s disease treatment.
“We know the underlying biology of
Alzheimer’s is complex, and therefore that effective treatment is likely going
to be a combination approach that will be personalized to each individual,”
said Dr. Snyder.
“The Alzheimer’s Association envisions
a time in the relatively near future when there are many approved treatments
that address Alzheimer’s in multiple ways across the entire course of the
disease, and that can be combined into powerful combination therapies that more
effectively slow and even stop the disease,” she added.
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