30 THE SCIENTIST | the-scientist.com
is very firmly in our minds that you have to
go before the onset of cognitive decline, and
you may be successful then in actually delay-
ing the onset of cognitive decline by five years,
which would be a major advance.”
Thanks to the recent development of
new detection technologies that yield more-
precise and reliable measurements of circu-
lating proteins, RNAs, and other molecules,
the field is hoping to do just that. Using these
analytic tools, which weren’t available just a
few years ago, multiple labs around the world
are now searching for new biomarkers of the
disease to develop blood tests that can screen
for early signs of Alzheimer’s, differentiate it
from conditions with similar symptoms, or
track its progression.
Finding patients in the early stages of the
disease and getting them into clinical trials
is researchers’ preliminary goal—and iden-
tifying biomarkers that can help do that is
“the low-hanging fruit,” says Anne Fagan, an
Alzheimer’s researcher at Washington Uni-
versity in St. Louis (WUSTL). Making clin-
ical diagnoses that aid treatment decisions,
which could involve the same or different
biomarkers than those used in trial screen-
ing and monitoring, will require a higher level
of accuracy—which Fagan, for one, doubts
can be attained with a blood test. “[When]
there’s a drug,” she says, “it’s going to be a
whole ’nother ballgame.”Biomarkers in clinical trials
AD is the most common type of dementia
and is characterized by cognitive decline,
worsening memory, and mood and behav-
ior changes. Although some controversy
remains about the underlying mechanisms
of Alzheimer’s, one idea known as the amy-
loid cascade hypothesis is widely accepted
in the field. It states that amyloid-β peptides
gradually aggregate as plaques between neu-
rons and kick off a sequence of pathological
processes. A major component of these amy-
loid plaques is an amyloid-β isoform called
Aβ42. Less Aβ42 is detected in the cerebro-
spinal fluid (CSF) of Alzheimer’s patients
than in healthy controls, likely because it’s
tangled up in plaques.
Aiming to enroll patients early in dis-
ease progression, recent trials have initially
identified people who show mild cognitiveand memory problems in clinical tests, and
then selected those who also have the telltale
plaques of amyloid-β in their brains accord-
ing to positron emission tomography (PET)
or decreased CSF levels of Aβ42. But that
process is onerous. A PET scan costs thou-
sands of dollars and is only available at major
medical centers in wealthy countries. While
the spinal tap needed to collect CSF is consid-
erably cheaper, the procedure is painful and
isn’t common at US doctors’ offices. A well-
validated blood test could make the entire
process of trial enrollment easier and more
efficient, and potentially allow researchers to
cheaply screen large numbers of healthy peo-
ple to identify those most at risk for Alzheim-
er’s before even mild symptoms have set in.
But the task has proven challenging. As
Fagan explains, unlike blood, CSF is in direct
contact with the brain, “so it’s much easier to
detect pathologic biomarkers from the CSF
than it would be for blood.”Early results using newer analysis tech-
nologies have shown promise, however. In
2018, researchers at VU University Medical
Center Amsterdam used a single-molecule
array called Simoa to test the plasma of peo-
ple who had normal scores on clinical tests
of cognition but reported having mem-
ory and cognitive lapses in their daily lives.^1
Lower ratios of Aβ42 to the most common
isoform of amyloid-β, Aβ40, in plasma were
associated with a higher risk of progression
to measurable cognitive impairment and to
dementia, including Alzheimer’s dementia,
the researchers found.
Although a blood test has never been
used in a selection process, certain blood-
borne markers of AD are already being
monitored in trials. Eli Lilly’s failed Phase 3solanezumab trial, for example, included
several blood draws from each patient over
the course of the trial for tests of Aβ42 and
Aβ40.^2 Fagan explains that the ratio between
the two isoforms (both in blood and in CSF)
can be a more accurate predictor of the dis-
ease than Aβ42 levels alone because people
who naturally make less Aβ42, but don’t have
Alzheimer’s, also typically make less Aβ40.
In a study published this August, Fagan,
her fellow WUSTL researcher Randall
Bateman, and colleagues reported that a
model combining plasma Aβ42:Aβ40, age,
and genetic factors was 94 percent accurate
in predicting whether a PET scan would
reveal existing amyloid plaques, and that
the plasma Aβ42:Aβ40 ratio was highly
predictive of which subjects would go on
to develop the plaques.^3 Other amyloid-β
isoforms, such as Aβ38, have also been
evaluated for whether they reflect amyloid
plaque burden.
Despite these promising results, the
Aβ42:Aβ40 ratio—and even amyloid plaques
themselves—remain imperfect predictors of
whether a given individual has the disease.
That’s due to patient-to-patient variation,
and to the complexity of Alzheimer’s.A heterogeneous disease
Decades of research have documented
the accumulation of amyloid plaques in
the brains of Alzheimer’s patients, but it’s
become clear that the condition has various
causes, says Walter Lukiw, a neuroscientist
at Louisiana State University. “It’s a disease
of neurons, [and] neurons can be killed in
many different ways,” he explains. “There’s
a huge number of factors that contribute to
the Alzheimer’s disease process.”
Among those factors is APOE ε 4 , a vari-
ant of a gene involved in cholesterol trans-
port also referred to as APOE4. The vari-
ant is associated with a heightened risk for
Alzheimer’s: at least one copy of APOE4 is
found in about half of patients with the dis-
ease, compared with 10–15 percent of the
general population. Age is also highly associ-
ated with an increased risk, but of course not
everyone who lives to be 90 will be affected,
and people with early-onset AD may exhibit
symptoms as early as their 40s. Research-
ers have also identified amyloid plaques inAt this point, I don’t think
we have the best idea in
terms of what biomarker
is exactly going to be
used for what.
—Michelle Mielke, Mayo Clinic