12.2019 | THE SCIENTIST 31© ISTOCK.COM, BRAINMASTER
the brains of some people who never develop
symptoms of Alzheimer’s, suggesting the
protein aggregations don’t always have clin-
ical relevance.
To wade through this heterogeneity,
King’s College London neuroscientist Abdul
Hye stresses the importance of stratifying
patients based on the nature of their disease.
Rather than discerning whether an individ-
ual fits under the Alzheimer’s umbrella, bio-
markers should identify underlying disease
mechanisms. “It’s not actually diagnosing
people but [asking] do they have the target
pathology?” he says. “If they do, we can then
select them for clinical trials early enough, if
there is a treatment available.”
There’s currently no shortage of candi-
date blood biomarkers for identifying dif-
ferent Alzheimer’s-associated pathologies.
In addition to levels and ratios of amyloid-β
isoforms, multiple research groups are inves-
tigating overall tau as well as phosphorylated
tau (p-tau), an abnormal form of the pro-
tein that can clump together in damaging
neurofibrillary tangles. A 2018 study, for
example, found that plasma levels of total tau
added predictive power to a model that also
included age, sex, and APOE4 allele status,
more accurately forecasting whether healthy
people were likely to develop Alzheimer’s
over a 12-year follow-up period.^4 Researchers
are also looking at more-general markers of
neuroinflammation and neurodegeneration.
(See illustration on page 28.)
According to Henrik Zetterberg, a bio-
markers researcher at the University of
Gothenburg in Sweden, improvements
in the analysis of protein composition in
blood samples have driven an explosion of
research—and promising results—over the
past decade. The new techniques include
Simoa, which Zetterberg helped develop
with the VU University Medical Center
team and is now commercially available,
as well as more-sensitive mass spectrome-
try assays. If validated, those candidates are
likely to feed the development not of a sin-
gle blood test for Alzheimer’s, but of multiple
specialized tests, researchers in the field s ay.
One biomarker or set of markers may be best
suited for identifying people with incipient
Alzheimer’s before symptoms start; another
for helping to rule out other conditions inpatients who’ve begun to exhibit Alzheim-
er’s symptoms; another for tracking pro-
gression; and still others for revealing what
mechanisms are driving a particular person’s
AD course.
“A s we are trying to discover and identify
these biomarkers, we’re also trying to figure
out where they g o ,” says Michelle Mielke, who
studies biomarkers in neurodegenerative dis-
ease at the Mayo Clinic in Rochester, Minne-
sota. “And at this point, I don’t think we have
the best idea in terms of what is exactly going
to be used for what.”
A number of questions and issues remain
to be resolved before many of the biomark-
ers found in the blood are ready for use in
trials, much less for clinical care, sources tell
The Scientist. One issue that researchers must
account for is individual variability, notes
Fagan. “People are so different [and] there’s
a lot of things we still don’t know how to even
control for in terms of statistical analyses.”
Age and APOE4 carrier status, for example,
can change the levels of some AD biomark-
ers independently of whether an individual
has the disease.
There are also technical challenges to
scaling up newer, highly sensitive assays to
yield results that are reliable and compa-
rable across sites. A current thrust of the
Alzheimer’s Disease Neuroimaging Initiative
(ADNI)—a multicenter, longitudinal study
aimed at identifying biomarkers for the
AD—is developing standard protocols forblood draws and sample processing to ensure
that differences in these steps don’t affect the
reliability of testing results, says Leslie Shaw,
a pathology researcher at the University of
Pennsylvania who codirects the biomarker
research component of the project.
In addition, the biomarker assays them-
selves need to be monitored for consistency,
Zetterberg says. “A s a lab, we run a number
of international standardization programs;
we work with all companies that are active
in [assays for Alzheimer’s biomarkers],” he
explains. The very need for these programs
is, in Zetterberg’s view, a positive sign of
progress toward reliable Alzheimer’s bio-
markers. There’s strong commercial inter-
est in developing such assays, and multiple
established analysis platforms exist for each
biomarker, he says, making him “very hope-
ful that this will be a viable field and eventu-
ally turn into clinical application.” gReferences- I.M.W. Verberk et al., “Plasma amyloid as
prescreener for the earliest Alzheimer pathological
changes,” Ann Neurol, 84:648–58, 2018. - L.S. Honig et al., “Trial of solanezumab for mild
dementia due to Alzheimer’s disease,” NEJM,
378:321–30, 2018. - S.E. Schindler et al., “High-precision plasma
β-amyloid 42/40 predicts current and future brain
amyloidosis,” Neurology, 93:e1647–59, 2019. - M. Pase et al., “Plasma tau corresponds to preclinical
Alzheimer’s disease and is a strong predictor of
future dementia,” Neurology, 90:S48.001, 2018.