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Neurodegenerative Diseases Alzheimer’s Disease
Are Biomarkers Valid as Surrogates for
Treatment Effects in Alzheimer’s Disease?
Philip Scheltens
Professor, and Director, Alzheimer Centre, VU Medical Centre
Abstract
Diagnosis of Alzheimer’s disease (AD), the most common form of dementia, involves neuropsychological testing, limited laboratory tests
and brain imaging. Current therapeutic options for AD are symptomatic treatments that target dysfunctional neurotransmitters associated
with the disorder. Recent research has focused on therapeutic strategies that inhibit the production and aggregation of amyloid beta
protein (Aβ) in plaques and increase its clearance from the brain. Such strategies are likely to be most effective at pre-clinical stages of the
disease, before widespread synaptic and neuronal loss occurs. Thus, there is a need for biomarkers that predict disease course and
outcome and monitor disease progression and treatment efficacy. The development of such biomarkers for AD is critical to translating the
efficacy of new therapies.
Keywords
Alzheimer’s disease, amyloid beta protein (Aβ), biomarkers, neurochemical, neuroimaging, magnetic resonance imaging (MRI), positron emission
tomography (PET), apolipoprotein E genotype, surrogate end-points
Disclosure: The author has no conflicts of interest to declare.
Received: 5 July 2009 Accepted: 28 August 2009
Correspondence: Philip Scheltens, Alzheimer Centre, VU Medical Centre, Postbus 7057, 1007 MB Amsterdam, The Netherlands. E: p.scheltens@vumc.nl
Alzheimer’s disease (AD) is a complex, heterogeneous age-related efficacy. Biomarkers could also identify AD at an early stage and
disorder and the most common form of dementia. It is characterised improve diagnosis. Biomarkers could also predict the disease course
clinically by a decline in cognitive and functional ability and the and outcome. Disorders such as diabetes have identifiable
development of behavioural and psychological symptoms. At a biomarkers that not only can be followed easily and repeatedly
cellular level, it comprises degeneration of neurons and synapses, for diagnosis, but also can monitor therapeutic response. The
formation of amyloid plaques and intracellular neurofibrillary tangles.
1
development of such biomarkers for AD is critical to translating
the efficacy of new therapies.
Diagnosis of AD requires neuropsychological testing, limited laboratory
tests and brain imaging. Since pathology generally precedes symptoms, This article will outline the challenges and limitations of the current
AD is diagnosed after clinical onset of the disease, at which stage knowledge of AD biomarkers and discuss the validity of biomarker
the patient is already suffering from cognitive defects such as mild candidates as surrogate end-points in clinical trials.
cognitive impairment (MCI).
2
Moreover, the diagnostic accuracy of
neurodegenerative disorders is low, ranging from 50 to 85%.
3
Requirements of Biomarkers
Biomarkers have typically been selected by a ‘candidate’ approach in
Current therapeutic options for AD are symptomatic treatments that which a hypothesis about the disease is tested in order to identify a
target dysfunctional neurotransmitters associated with the disorder. gene or molecular component of the disease process.
3
Established
The only approved therapies are cholinesterase inhibitors and one criteria exist for potential biomarkers of AD: they should reflect a
N-methyl-D-aspartate receptor antagonist. Use of these agents is neuropathological characteristic of AD and should be validated in
widespread and long-term;
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however, they confer only moderate patients with independently diagnosed AD pathology. Ideally, they
clinical effects in patients with mildly to moderately severe symptoms should have sensitivity of ≥85% and specificity (to differentiate from
and do not affect the fundamental pathology of AD.
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The majority of controls and other forms of dementia) of ≥75%.
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recent research has focused on therapeutic strategies that inhibit the
production and aggregation of amyloid beta protein (Aβ) in plaques Neurochemical Biomarkers
and increase its clearance from the brain. Such strategies are likely It is widely considered that the deposition of Aβ peptides in the brain
to be most effective at pre-clinical stages of the disease, before is a key event in the pathogenesis of AD, and Aβ is secreted by cells,
widespread synaptic and neuronal loss occurs.
1
therefore it is a logical choice of biomarker. It is the main component
of AD plaques and generally has a length of 42 or 40 amino acids
Therefore, there is a need for biomarkers that predict the disease (Aβ
1–42
and Aβ
1–40
). A number of studies, involving a total of around
course and outcome and monitor disease progression and treatment 2,000 patients and controls, demonstrate a 50% reduction of Aβ
1–42
in
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