6 November 2021 | New Scientist | 47tricky. Tau can also take many different forms,
and it is unclear which are the best to target.
A few trials of tau-targeting antibodies have
failed, but other therapies are in development.
In the meantime, there are things we can
do to reduce our risk of accumulating harmful
tau tangles. Sigurdsson says there has been
relatively little research on how lifestyle factors
affect tau pathology, but that in general “what’s
good for your heart is good for your brain”.Clues in our genes
Genes clearly play a part in Alzheimer’s disease,
because a small proportion of cases occur
earlier in life, as a result of specific genetic
mutations. These are exceedingly rare – about
5 to 6 per cent of Alzheimer’s cases are early
onset and only a fraction of these are caused
by the mutations. But there are many more
common gene mutations loosely connected
with late-onset Alzheimer’s disease. The gene
with variants most commonly associated with
late-onset disease is called apolipoprotein E
(APOE): the APOE e2 variant reduces risk and
the APOE e4 variant increases it.
Researchers are studying the roles of APOE.
The e4 variant seems to promote formation of
beta-amyloid plaques and may also increase
neuroinflammation that affects the function
of the blood-brain barrier, the protective layer
that controls the movement of molecules and
cells between the brain and the bloodstream.
While some strategies targeting APOE seem
promising in animals with Alzheimer’s-like
illness, very few have been tested on humans.
One especially interesting early stage trial is
now testing whether a therapy that delivers
the protective APOE e2 gene has any beneficial
effects for people who carry two copies of
the harmful APOE e4 variant.
Unfortunately, for now, there is nothing
you can do about your genes, and genetic
testing for APOE variants isn’t generally
advised. That is because it doesn’t definitively
determine whether you will get the disease –
plenty of people with the protective form
still get Alzheimer’s and plenty with the
risk-enhancing form never do.Outside invaders
Infections may also play a role in the likelihood
of someone developing Alzheimer’s. Although
there have been conflicting findings over
the years, evidence is building that certain
viruses and bacteria increase risk.
In particular, research has implicatedin the 1990s after the discovery of three rare
genetic mutations involved in the formation
of beta-amyloid. Having one of these
essentially guarantees that a person gets
early-onset Alzheimer’s – when the disease
occurs before the age of 65. Since beta-amyloid
plaques in the brain are a hallmark of the
disease, it seemed likely this was the culprit.
Other contributing factors were acknowledged,
but the idea was that these followed the initial
problem with amyloid, in what is known as
the “amyloid cascade” hypothesis.
So far, amyloid-busting drugs have failed to
actually improve symptoms of the disease. But
some experts hope they might yet be effective,
if they are given before symptoms appear – and
other candidates are now in late-stage trials.
Rudolph Tanzi, who studies the molecular
genetics of Alzheimer’s at Harvard University,
says the thinking now is that the role of
amyloid in Alzheimer’s is similar to the role
of cholesterol in heart disease, in that levels
are elevated for decades before the onset of
symptoms. If doctors can spot high cholesterol
levels early, they can prescribe medications to
lower them and prevent heart damage. But once
a person has severe congestive heart failure,
these drugs will be insufficient. It isn’t routine
for doctors to measure beta-amyloid levels in
people, so by the time someone has symptoms
of Alzheimer’s, clearing up plaques won’t undo
the damage. Many people are searching for
biomarkers to help us detect the disease years
before symptoms appear, and so give these
preventive treatments a fighting chance.
Tangled up in tau
Beyond beta-amyloid, another major hallmark
of Alzheimer’s in the brain is accumulation
of a protein called tau. In healthy brains, tau
helps to support the structure of neurons, but
certain changes can cause it to clump together
inside axons (the arms connecting the main
body of a neuron to other cells), interfering
with a neuron’s ability to communicate.
Once people develop Alzheimer’s, the
amount of tau build-up actually correlates
better with dementia severity than the amount
of beta-amyloid, which suggests it plays an
important role in the progression of the
disease once symptoms have begun, says Einar
Sigurdsson at New York University. “Targeting
tau is probably a more feasible approach in
the later stages of the disease,” he says.
Unfortunately, here too, we don’t yet have
any successful drugs. As the vast majority of
tau build-up is inside neurons, targeting it is >