Scientific American - February 2019

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THE NEWS FROM THE EXPERTS

New Strategy

for Alzheimer’s

We need better molecular biomarkers

to create targeted drugs

By Howard M. Fillit

Alzheimer’s disease is the sixth leading cause of death in the
U.S., and unlike with cancer and heart disease, we lack the tools
to effectively diagnose and treat it. In sharp contrast to other ill-
nesses and despite many efforts, huge expense and hundreds of
clinical trials, no new treatments have been ap proved in the past
16 years. The emphasis has been on drugs targeting beta-amy-
loid proteins, which clump into plaques in the brains of afflicted
people. Unfortunately, these approaches have not
yet yielded the results we hoped for.
So now it is time to target novel pathways to tack-
le this incredibly complex disease. This has been a
challenge because of the absence of affordable and
non in vasive tests based on biomarkers that doctors
can easily use in their offices. The alternatives have
been expensive and invasive spinal taps or neuro-
imaging tests that can be performed only in a hospi-
tal or freestanding radiology office. New biomarkers
are needed for specific molecular targets that can be
used to subtype patients; for predicting the likeli-
hood that they will acquire Alzheimer’s; and possibly
for providing a diagnosis even before symptoms are
noticeable, enabling prevention. That is, they could
do what currently available amyloid positron-emis-
sion tomography (PET) scans and cerebrospinal flu-
id tests do. Biomarkers can also be used to enroll pa-
tients in clinical trials directed to a specific target,
such as beta-amyloid, and to measure how the body
responds to a treatment—as was done most recently
by Biogen with its anti-beta-amyloid monoclonal an-
tibody. Ultimately biomarkers can determine which therapies
would be most effective for an individual.
Such tools are already available for other diseases, including
diabetes, hypertension, hyperlipidemia and cancer. In heart dis-
ease, for in stance, serum cholesterol levels, which are measured
after simply drawing blood with a needle stick, have long been
used as a biomarker to identify patients at risk. The test is afford-
able and generally covered by employers or health insurance pro-
viders, including Medicare. If blood levels are high, drugs such as
statins can be prescribed to lower cholesterol and with it the risk
for heart disease. Doctors can also use cholesterol levels to see if
a prescribed drug is working or needs an adjustment. LDL cho-
lesterol is also recognized as a biomarker for heart disease risk by
the Food and Drug Administration, so clinical trials can show
that a drug lowers cholesterol and get approval for it.

Despite the existing tests for diagnostic and prognostic bio-

markers, few patients in the U.S. have been tested with these con-

firmatory tests because of cost and access restrictions. And payers,

including Medicare, will not cover amyloid PET scans, based on

the perception that a definitive diagnosis has little clinical value.

But recent studies on the value of PET beta-amyloid brain

scans, supported by the Centers for Medicare  & Medicaid Servic-

es, have shown that practicing “dementia expert” doctors mis-

diagnose Alzheimer’s in about 50  percent of cases and change

their management and treatment of patients nearly 70 percent of

the time when this test is used. An inexpensive blood test, covered

by insurance, which can be performed in any clinical setting,

would have a big impact on patients and their caregivers.

Recently the FDA issued guidelines recognizing the important

role of biomarkers in demonstrating efficacy in clinical trials for

Alzheimer’s (especially early-stage ones). These new guidelines

are a major step forward for fast-tracking drugs for the disease.

We need comparable tests—preferably blood tests—to help

diagnose Alzheimer’s and evaluate treatments. This will aid us in

making clinical trials more rigorous, affordable and efficient,

will accelerate drug development and will improve clinical care

by providing access to accurate diagnoses. A new initiative called

the Diagnostics Accelerator, under the auspices of the Alzhei-

mer’s Drug Discovery Foundation, aims to develop novel bio-

markers from blood and accessible fluids and tissue. Such mark-

ers, specifically tied to Alzheimer’s or other forms of dementia,

will allow us to predict more accurately which treatment and pre-

vention strategies will work in at-risk populations, as we can now

do in cancer, heart disease and other diseases of aging.

Illustration by Benjamin Currie

Howard M. Fillit is founding executive direc tor and chief

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