By Carly Cassella
Sciencealert
-- January 11, 2021 -- Alzheimer's Disease (AD) is probably more diverse than
our traditional models suggest.
Postmortem, RNA sequencing has revealed
three major molecular subtypes of the disease, each of which presents
differently in the brain and which holds a unique genetic risk.
Such knowledge could help us predict who
is most vulnerable to each subtype, how their disease might progress and what
treatments might suit them best, potentially leading to better outcomes.
It could also help explain why effective
treatments for AD have proved so challenging to find thus far.
The mouse models we currently have for
pharmaceutical research match a particular subset of AD, the authors found, but
not all subtypes simultaneously.
This may "partially explain why a
vast majority of drugs that succeeded in specific mouse models do not align
with generalized human trials across all AD subtypes," they say.
"Therefore," the authors conclude,
"subtyping patients with AD is a critical step toward precision medicine
for this devastating disease."
Traditionally, AD is thought to be marked
by clumps of amyloid-beta plaques (Aβ), as well as tangles of tau proteins
(NFTs) found in postmortem biopsies of the brain.
Both of these markers have become
synonymous with the disease, but in recent years our leading hypotheses about
what they actually do to our brains have come under question.
Typically, accumulations of Aβ and NFT
are thought to drive neuronal and synaptic loss, predominantly within the
cerebral cortex and hippocampus. Further degeneration then follows, including
inflammation and degeneration of nerve cells' protective coating, which causes
signals in our brains to slow down.
Strangely enough, however, recent evidence
has shown up to a third of patients with a confirmed, clinical diagnosis have
no Aβ plaques in postmortem biopsies. What's more, many of those found with
plaques at death did not show cognitive impairment in life.
Instead of being an early trigger of AD,
setting off neurodegeneration and driving memory loss and confusion, in some
people, Aβ plaques appear to be latecomers.
On the other hand, recent evidence suggests
tau proteins are there from the very earliest stages.
In light of all this research, it's
highly likely there are specific subtypes of AD that we simply haven't teased
apart yet. The new research has helped unbraid three major strands.
To do this, researchers analyzed 1,543
transcriptomes - the genetic processes being express in the cell - across five
brain regions, which were collected post mortem from two AD cohorts.
Using RNA sequencing to profile these transcriptomes,
the authors identified three major molecular subtypes of AD, which correspond
to different dysregulated pathways.
These include: susceptibility to
tau-mediated neurodegeneration; amyloid-β neuroinflammation; synaptic
signaling; immune activity; mitochondria organization; and myelination.
All of the subtypes were both
independent of age and disease severity. Their molecular signatures were also
present in all brain regions, but especially so in the hippocampus, which is
largely associated with forming new memories.
What's more, Aβ and tau proteins could
not fully explain the different subtypes, which suggests cognitive impairment
"is neither dependent on nor fully assured by" by their accumulation
in the brain.
In fact, only about a third of AD cases
carried these consistent hallmarks of a 'typical' AD presentation. The rest of
the cases showed opposite forms of gene regulation within molecules, which
caused complex changes in multiple brain pathways and cell types.
"It is more likely that Aβ and tau
accumulation are often mediators or the end effects of neurodegeneration and
inflammation, independent of hippocampal load," the authors write.
In other words, the mere presence of Aβ
and tau clumps might not be as important as the way they interact with each
other and other cell processes.
Comparing the results to current mouse
models, the authors found a serious mismatch. Most mouse models used in
clinical research are based on 'typical' presentations of AD, which would only
cover a third of the cases in this study.
This means treatments tested on mice may
not work for all patients. To develop a more personalized approach to
treatment, scientists have been trying to identify and verify molecular
biomarkers just like these.
"As we have shown, AD subtypes have
very different transcriptomic signatures and therefore will likely require
specialized treatments," the authors conclude.
"Given that many subtype-specific
key regulators have opposite directions in some AD subtypes, it is also
possible that drugs that reduce AD symptoms in one subtype may exacerbate
symptoms in another subtype."
Further research is needed to confirm
this idea, but that's just the sort of information we really need to know.
The study was published in the Science
Advances.
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