Biomarkers in Alzheimer’s Disease—Perspectives for the Future
Biomarkers in Alzheimer’s Disease—Perspectives for the Future
US Neurology, 2010;6(1):23-7
Abstract
Alzheimer’s disease (AD) is characterized pathologically by the overproduction or excessive accumulation of amyloid beta protein leading to the deposition of diffuse and neuriric plaques. Hyperphosphorylation of tau protein promotes the accumulation of intracellular neurofibrillary tangles. These events comprise a pathological cascade in the AD brain that includes oxidation, inflammation, excitotoxicity, and apoptosis with activation of myriad associated intracellular pathways. Some of these neuropathological changes are detectable by biomarkers such as neuroimaging or serum or cerebrospinal fluid (CSF) measures. Magnetic resonance imaging (MRI) reveals cerebral atrophy, fluorodeoxyglucose positron emission tomography (FDG-PET) shows regional brain hypometabolism, amyloid imaging demonstrates fibrillar amyloid in plaques, and CSF measures reveal decreased levels of the amyloid protein and increased levels of total tau protein and hyperphosphorylated tau. These biomarkers provide the basis for identifying and characterizing asymptomatic pre-clinical AD pathology, minimally symptomatic prodromal AD, and AD type dementia. Biomarkers have an increasingly important role in AD care and research at all stages of disease, and promise to assist in the development of new AD therapies.
Keywords
Alzheimer’s disease, drug development, biomarkers, cerebrospinal fluid, amyoid imaging, fluorodeoxyglucose positron emission tomography, magnetic resonance imaging, target engagement, pharmaceutical industry, differential diagnosis, prognosis
Disclosure: Jeffrey L Cummings, MD, has consulted for Bayer Pharmaceuticals.
Acknowledgments: Jeffrey L Cummings, MD, is supported by the Sidell-Kagan Foundation, the Jim Easton Gift, a California Alzheimer’s Disease Center grant, and a National Institute on Aging (NIA) Alzheimer’s Disease Research Center grant (P50 AG16570). Irma Hernandez assisted with manuscript preparation.
Received: April 26, 2010 Accepted: June 25, 2010 Citation: US Neurology, 2010;6(1):23–27
Correspondence: Jeffrey L Cummings, MD, Lou Ruvo Center for Brain Health, 888 West Bonneville, Las Vegas, NV 89106. E: cumminj@ccf.org
There has been remarkable progress in developing biological markers (biomarkers) that provide insight into the progression of Alzheimer’s disease (AD). Biomarkers document the course of AD from structural, functional, molecular, and chemical perspectives, and promise to assist in the development and monitoring of new therapies. Biomarkers have become particularly important to AD drug development for their potential to establish efficacy in periods of time shorter than required to demonstrate clinical efficacy and to support a disease-modification claim when applying to the US Food and Drug Administration (FDA) as a disease-modifying treatment of AD.
This article describes the currently available biomarkers and their role in clinical practice and research, and discusses some of the anticipated applications of biomarkers for AD. Disease-course biomarkers and drugactivity biomarkers are emphasised. The use of biomarkers to monitor adverse events and other aspects of drug development are presented.
Definition of Biomarkers
A biomarker is defined as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.1 Biomarkers include neuroimaging, cerebrospinal fluid (CSF) measures, blood-based assessments, and, in some cases, urinary or salivary measures. The definition emphasizes several major aspects that must be considered when choosing and using biomarkers. A biomarker must be objectively measured; this implies that collection, storage, standards, and reference methodologies are available. The biomarker is an indicator of a biological process, disease, or therapy; the biomarker is a limited window on a process or response that is viewed as a guide to the disease processes ongoing in the brain or body.
In the case of AD, biomarkers provide documentation of brain atrophy, reduced brain metabolism, changed brain activation, deposition of fibrillar amyloid, alterations in CSF constituents, or alterations in serum measures.2
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Alzheimer’s disease, drug development, biomarkers, cerebrospinal fluid, amyoid imaging, fluorodeoxyglucose positron emission tomography, magnetic resonance imaging, target engagement, pharmaceutical industry, differential diagnosis, prognosis
