Alzheimer's
Early Detection Strategies--From Skin to Sniff Tests
and Beyond
September 14, 2006
Much
is still not understood about Alzheimer’s disease
(AD), the progressive neurodegenerative disorder that
robs an estimated 4.5 million Americans of their
memory and basic cognitive functions, their
independence, and ultimately their lives. But one
thing is abundantly clear—the earlier AD is detected
and drug treatment is initiated, the better the
chances of slowing the disease’s destructive
trajectory (Marseille, Am J Alzheimer’s Dis,
2006).
The
statistics are staggering. The number of Americans
with AD has more than doubled since 1980 and is
projected to grow to as many as 16 million by 2050.
According to the National Institute on Aging, approximately
5% of people aged 65 to 74 years have AD, and nearly
half of those 85 years of age or older may have the
disease. These figures do not, however, include the
millions of people with mild cognitive impairment
(MCI), a pre-dementia disorder that progresses to AD
in approximately 80% of cases (Tarkan, The New York
Times, 2005).
As
the first wave of Baby Boomers turns 60, the
prevalence of AD will likely continue to rise. This
prospect has spawned a huge research effort to clarify
the pathological basis of AD, identify early
biochemical changes and drug targets in the brain, and
develop new, more effective therapies. In 2006, the
US
government spent an estimated $650 million on
Alzheimer’s disease research (Allday, San
Francisco Chronicle, 2006).
Exploring New Options
Key
strategies being explored for early diagnosis and risk
assessment of AD include genetic tests to identify an
inherited predisposition to the disease, brain imaging
modalities to detect subtle changes in brain structure
and function, and biochemical assays targeting
biomarkers of AD in blood, urine, saliva, and
cerebrospinal fluid (CSF). At present, diagnosis
relies largely on patient history, written or oral
neuropsychological tests to detect deficits in memory
and cognitive function, and imaging studies.
No
available test is definitive for AD—other than
postmortem autopsy findings in brain tissue. The
combination of imaging studies and biomarker assays
currently offers the most promise for early and
specific diagnosis of AD (Mosconi, Expert Rev
Neurother, 2004, and Fagan, Ann Neurol,
2006).
Recently,
the identification of a protein biomarker in
fibroblasts that can distinguish between AD and other
forms of dementia during the first year or two of the
disease generated a lot of excitement. This finding
holds hope for a simple skin test for early stage AD.
Fibroblasts from patients with AD, when exposed to an
inflammatory stimulus, have a markedly different MAP
kinase Erk 1/2 response (Khan, PNAS, 2006).
Another
intriguing diagnostic strategy in development targets
a person’s sense of smell. The neurons in the area
of the brain involved in smell are one of the first
casualties of AD pathology. A 2000 study showed that
in patients with mild cognitive impairment, poor
olfactory identification, especially in individuals
who are not aware they have a problem detecting odors,
is predictive of AD. (Devanand, Am J Psychiatry,
2000). A simple scratch-and-sniff test could hold the
key to early AD diagnosis.
Visualizing Brain
Pathology
Magnetic
resonance imaging (MRI) can be used to help predict
whether patients with memory loss and cognitive
impairment will progress to AD. (Killiany, Ann
Neurol, 2000). In fact, MRI scans to determine
hippocampal volume may be able to detect AD decades
before the first clinical symptoms of dementia appear
(Gosche, Neurology, 2002).
Researchers
at the Mayo Clinic are developing an intravenous MRI
contrast agent—a derivative of human beta-amyloid—that
selectively targets amyloid plaques in the brain and
has high blood-brain barrier permeability (Poduslo, Biochemistry,
2004).
Diagnostic
imaging techniques based on positron emission
tomography (PET) rely on identifying diminished
glucose utilization in specific regions of the brain.
Altered glucose metabolism has been associated with
cognitive dysfunction and neurodegenerative diseases
such as AD (Silverman, JAMA, 2001).
Another
imaging technique, single-photon emission computed
tomography (SPECT) can differentiate AD from other
forms of dementia (Bonte FJ, J Nucl Med, 2004).
AD patients often exhibit reduced blood flow in the
posterior cingulate cortex early in the course of the
disease. SPECT can detect this reduction in blood
flow.
A
Phase II clinical trial of 123-I IMPY, an engineered
compound injected into the bloodstream that attaches
to beta-amyloid in the brain, is currently recruiting
patients and has a scheduled completion date of June
2007. The compound carries a radioactive tag and is
detectable by PET or SPECT.
Targeting
Disease-Specific Biomarkers
No
genetic biomarker identified to date is diagnostic for
Alzheimer’s disease, but inheritance of ApoE-4, one
form of the apolipoprotein E gene, is an established
risk factor and an important tool used to confirm a
suspected diagnosis (Mayeux, N Engl J Med,
1998). Inheritance of the E4 allele from one parent
increases a person’s AD risk by about 3-fold, while
two copies of the E4 gene yields a 14-fold increased
risk.
Other
genetic biomarkers with diagnostic potential are in
various stages of research and development. (See
Table: Selected Diagnostic Tests for AD) Oxford,
U.K.-based Synaptica Ltd. is developing a diagnostic
test for early stage AD based on proprietary
technology used to test for novel genetic markers
predictive of AD risk.
Protein
biomarkers of disease in serum and other bodily fluids
and tissues are one of the hottest areas of research
today, with tremendous untapped potential for
identifying novel drug targets, developing highly
specific diagnostic tests, and monitoring disease
progression and treatment response. At present, levels
of beta-amyloid, tau, and phospho-tau protein are the
most promising biomarkers for AD diagnosis (Galasko, J
Alz Dis, 2005).
Recent
studies suggest that quantitative multiplexed
proteomic methods will be able to identify panels of
biomarkers in the CSF that can distinguish patients
with AD from healthy patients and from those with
other neurodegenerative diseases such as Parkinson’s
disease and Lewy body dementia (Abdi, J Alz Dis,
2006 and Zhang, J Alz Dis, 2005).
The
ADmark Alzheimer’s Evaluation test from Athena
Diagnostics detects ApoE2, E3, and E4 alleles and
measures the levels of phosphorylated-tau protein,
total-tau protein, and beta-amyloid-42 (a “sticky”
form of beta-amyloid that aggregates to form plaques).
Nymox’s
AlzheimAlert is an ELISA-based test that measures the
level of neural thread protein (AD7C-NTP) in
first-morning urine samples. AD7C-NTP is a brain
protein present in elevated levels in the urine of
people with AD. Over-expression of NTP is associated
with cell death (Munzar, Neurol Clin Neurophysiol,
2002).
Applied
NeuroSolutions is collaborating with Nanosphere to
develop a diagnostic test for AD based on
Nanosphere’s patented Biobarcode technology and
Applied NeuroSolutions’ proprietary AD biomarkers.
Biobarcode technology utilizes antibody-linked gold
nanoparticles containing DNA “barcodes” that
amplify a protein signal, enabling highly sensitive
protein detection. Nanosphere is developing an AD
diagnostic test based on antibodies that target
amyloid-beta-derived diffusible ligands (ADDLs), which
are present in elevated levels in the AD brain.
Applied
NeuroSolutions’ antibody-based diagnostic test
detects altered tau protein (ptau-23) in the CSF of
patients with AD.
The
NuroPro blood test, being developed by Power3 Medical
Products, is designed for early detection of several
neurodegenerative diseases, measures the concentration
of nine proteins in serum and can distinguish between
Alzheimer’s disease, amyotrophic lateral sclerosis (ALS),
and Parkinson’s disease. The test monitors the
concentrations of proteins released into the blood
upon cell death.
SYN-X
Pharma’s patented immunoassay for AD diagnosis
involves direct detection of human glutamine
synthetase in blood and other bodily fluids. The test
can distinguish between AD and non-AD dementia.
A Booming Need
The
market for AD drug therapy in the
US
, Europe, and
Japan
exceeded $3 billion in 2005, according to Millennium
Research Group. By 2009, approximately 10 million
people in this global market will suffer from
Alzheimer’s disease.
A new
crop of drugs in development aimed at preventing and
combating the characteristic build-up in the brain of
amyloid plaque is expected to come to market by 2011,
according to Navigant Consulting.
Clearly,
the more accurately clinicians can predict the
likelihood of progression from MCI to Alzheimer’s
disease and the earlier AD can be detected—well
before the formation of amyloid plaques compromises
brain function and causes memory loss and other
clinical symptoms to appear—the
more effective these new treatments are likely to be.
As the average age of the
US
population rises, Alzheimer’s disease represents a
growing healthcare crisis.
References
Abdi,
F, et al. Detection of biomarkers with a multiplex
quantitative proteomic platform in cerebrospinal fluid
of patients with neurodegenerative disorders. J Alz
Dis. 2006;9(3):293–348.
Allday,
E. “Studies bloom on Alzheimer’s as Boomers
age.” San Francisco Chronicle. May 15, 2006.
Bonte,
FJ, et al. Differential diagnosis between
Alzheimer’s and frontotemporal disease by the
posterior cingulated sign. J Nucl Med.
2004;45(5):771–774.
Devanand,
DP, et al. Olfactory deficits in patients with mild
cognitive impairment predict Alzheimer’s disease at
follow-up. Am J Psychiatry. 2000;157(9):1399–1405.
Fagan,
AM, et al. Inverse relation between in vivo amyloid
imaging load and cerebrospinal fluid amyloid-beta42
in humans. Ann Neurol 2006;59(3):512–519.
Galasko,
D. Biomarkers for Alzheimer’s disease—clinical
needs and application. J Alz Dis. 2005;8(4):339–346.
Gosche,
KM, et al. Hippocampal volume as an index of Alzheimer
neuropathology: findings from the Nun study. Neurology.
2002;58(10):1476–1482.
Khan,
TK and Alkon, DL. An internally controlled peripheral biomarker for Alzheimer's disease:
Erk1 and Erk2 responses to the inflammatory signal
bradykinin. PNAS 2006;103(35):13203–13207.
Killiany,
RJ, et al. Use of structural magnetic resonance
imaging to predict who will get Alzheimer’s disease.
Ann Neurol. 2000;47(4):430–439.
Marseille,
DM and Silverman, D. Recognition and treatment of
Alzheimer’s disease: a case-based review. Am J
Alzheimer’s Dis. 2006;21(2):119–125.
Mayeux,
R, et al. Utility of the apolipoprotein E genotype in
the diagnosis of Alzheimer’s disease. N Engl J
Med 1998;338(8):506–511.
Mosconi,
L et al. Magnetic resonance and PET studies in the
early diagnosis of Alzheimer’s disease. Expert
Rev Neurother 2004;4(5):831–849.
Munzar,
M, et al. Clinical
study of a urinary competitve ELISA for neural thread
protein in Alzheimer disease. Neurol Clin
Neurophysiol. 2002;20(1):2–8.
Poduslo,
JF, et al. Design and chemical synthesis of a magnetic
resonance contrast agent with enhanced in vitro
binding, high blood-brain permeability, and in vivo
targeting to Alzheimer’s disease amyloid plaques. Biochemistry.
2004;43(20):6064–6075.
Silverman,
DHS, et al. Positron emission tomography in evaluation
of dementia: regional brain metabolism and long-term
outcome. JAMA. 2001;286:2120–2127.
Tarkan,
L. “Predicting Alzheimer’s is more with than
reality.” The New York Times. Oct. 25, 2005.
Zhang,
J, et al. Proteomic biomarker discovery in
cerebrospinal fluid for neurodegenerative diseases. J
Alz Dis. 2005;8(4):377–386.
Selected
Diagnostic Tests for AD
Company
|
Diagnostic Test
|
Target
|
|
Applied
NeuroSolutions
|
Antibody-based
assay; commercial collaboration with Nanosphere
|
altered
tau protein (ptau-23) in CSF
|
|
Athena
Diagnostics
|
ADmark
Alzheimer’s Evaluation test
|
ApoE2,
E3, and E4; phosphorylated-tau protein, total-tau
protein, beta-amyloid-42
|
|
DiaGenic
|
Blood-based gene
expression analysis
|
Pattern of gene
expression
|
|
Nanosphere
|
Biobarcode-based
protein biomarker detection
|
amyloid-beta-derived
diffusible ligands (ADDLs)
|
|
Nymox
|
AlzheimAlert
(ELISA)
|
Neural
thread protein (AD7C-NTP)
|
|
Power3
Medical Products
|
NuroPro
|
Panel
of 9 serum proteins
|
|
Synaptica
Ltd.
|
Genetic
biomarkers
|
|
|
SYN-X
Pharma
|
Immunoassay
|
human
glutamine synthetase in blood
|
Source:
Vicki Glaser
|
