Cover Story
The search for the perfect blockbuster biomarker for Alzheimer’s Disease is on and many companies are contributing to the search.
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Alzheimer’s disease (AD) does not arise overnight. It’s an insidiously progressive neurodegenerative disease that requires decades of pathological progression to become manifest. AD may initially present as mild cognitive impairment (MCI), a disorder that frequently progresses on to AD within three to five years.
Pushing back the clock even earlier, autopsy studies suggest the pathology of AD may begin accumulating well before the patient shows any symptoms. This pre-symptomatic condition presents an ideal window for therapeutic intervention, but also presents a significant challenge to identify patients before potentially irreversible damage occurs. And that’s where biomarkers for AD come into the picture.
Demand for improved biomarkers for AD stems from two rising tides. First, pharmaceutical companies need better tools to facilitate development of novel disease-modifying AD therapeutics, and second, patients and their physicians need better tools for early and accurate diagnosis of AD.1
Performance of potential biomarkers for AD can be characterized in prodromal AD patients (MCI) and in presymptomatic AD patients. For example, in genetic forms of the disease, it is possible to study family members carrying disease-carrying mutations prior to symptomatic onset.
An ideal biomarker should successfully identify patients in populations who are at the greatest risk of developing symptomatic AD. Thus the biomarker should reflect changes seen in these earliest stages of disease, and must target a disease process upstream of symptomatic development.2
Biomarkers under development
The two hallmark pathological lesions of AD are the accumulation of aggregated Aß peptide in amyloid plaques, and the accumulation of hyperphosphorylated tau filaments in intracellular neurofibrillary tangles. Both tau and Aß define the disease pathology of AD. They are pathogenically-linked to disease in animal models, and genetically-linked to neurodegeneration in humans. Thus, these two targets provide an excellent starting point for biomarker development.
Amyloid plaques are particularly promising as a biomarker, not only because they are a histopathological hallmark of AD, but also because the aggregated Aß that composes them might play a key role in the pathogenesis of AD (summarized by the amyloid hypothesis)3. The most direct evidence supporting this hypothesis stems from studies of gene mutations that cause autosomal-dominant-inherited forms of AD. These mutations all lead to increased production and accumulation of specific Aß species (Aß42), either through effects on the amyloid precursor protein (APP) itself, or through effects on presenilin-1 or presenilin-2, which form part of one of the proteolytic complexes that cleaves APP to generate Aß. Aß pathology defines the diagnosis of AD, plays a key role in the pathogenesis of AD, and develops prior to symptomatic manifestations of AD. For these reasons, there has been great interest in developing therapies and diagnostic tools aimed at Aß.
Indeed, drugs that block the production of Aß known as ß- and ß-secretase inhibitors inhibit or reverse its deposition (metal-chelators and plaque-solubilizers) or increase its clearance (Aß antibody therapy) are currently under development. These drug development programs have driven significant interest in developing biomarkers for Aß and amyloid plaques.
For example, Aß levels can be measured in the cerebrospinal fluid (CSF) and while total Aß levels in the CSF are not significantly changed in AD, levels of the longer, more amyloidogenic form of Aß, Aß42, are decreased in AD. It is thought that this decrease in Aß42 reflects trapping of Aß42 in the amyloid plaques in the brain.
Indeed, studies suggest that decreased CSF Aß42 correlates well with the levels of amyloid plaques in the AD brain as determined by amyloid imaging4. Decreased CSF Aß42 also appears to be an early marker for AD, and might predict conversion to AD when combined with CSF tau measures5.
Amyloid imaging
A variety of ligands for molecular imaging of amyloid plaque accumulation have been proposed. To date, the most successful imaging approach has utilized the 11C-labeled positron emission tomography (PET) tracer 6-OH-BTA, also known as Pittsburgh compound B or PIB, developed by Drs. Chester Mathis and William Klunk at the University of Pittsburgh. A large number of studies have validated this 11C compound as an excellent ligand for amyloid plaque imaging.6,7 Based on these studies, amyloid imaging appears to meet many of the baseline criteria for a blockbuster biomarker: Amyloid imaging is sensitive and specific for AD, with good test-retest reliability.
In addition, amyloid deposition precedes symptomatic development of AD and amyloid imaging might predict which MCI patients are most likely to convert to AD. Amyloid imaging is also likely to be useful in selecting which patients to treat with amyloid- lowering drugs, and reflect efficacy of treatment with such drugs. However, the 11C isotope used in these studies has only a 20-minute half-life, presenting a significant impediment to widespread clinical application. That’s why researchers at companies such as Avid Radiopharmaceuticals, Philadelphia, GE Healthcare, UK, and Siemens Medical Solutions, Malvern, Pa., have focused on developing 18F-labeled radiopharmaceuticals with a two-hour half-life for AD brain imaging.
The first such ligand, FDDNP, was developed by Dr. Jorge Barrio and colleagues at the University of California, Los Angeles and is under development by Siemens. It images amyloid plaques and neurofibrillary tangles, and shows promise in differentiating mild cognitive impairment patients from normal controls and AD patients.8
Working with Dr. Hank Kung and colleagues at the University of Pennsylvania, Avid Radio-pharmaceuticals has also developed and characterized 18F-AV-1 as a potential amyloid imaging agent. Early clinical trials for 18F-AV-1, presented by Dr. Chris Rowe and colleagues at the 2007 SNM meeting, show clear differentiation between AD and control subjects.9 This agent, which Avid has partnered with Bayer-Schering Pharmaceuticals, Germany, labels only amyloid plaques, and early data suggest it can detect amyloid very early in disease progression, even in pre-symptomatic individuals. Avid has also begun clinical trials on a number of second-generation agents for imaging plaques. An 18F version of PIB has also recently been reported by Mathis and colleagues at the same meeting10, and GE will soon begin clinical trials aimed at developing this ligand.
Since PET imaging with 18F-labeled radiopharmaceuticals is already widely used for cancer imaging (more than 1.5 million scans were done in 2006), these 18F amyloid imaging ligands show incredible promise for meeting all the baseline criteria for a blockbuster biomarker for AD.
Tau as a biomarker
Tau pathology is the other prominent feature of Alzheimer’s disease, and is also prominent in a variety of other related neurodegenerative diseases, including Pick’s disease (PiD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and frontal temporal dementia with parkinsonism linked to chromosome 17 (FTDP-17).
Each of these related diseases, known as tauopathies, is defined by specific regional and cellular distributions of abnormally aggregated tau filaments. There is now unequivocal evidence demonstrating that abnormalities in tau are sufficient to cause neurodegenerative disease, since mutations in the gene for tau cause FTDP-17.
Tau is a microtubule-associated protein that binds to and stabilizes microtubules. More than 30 distinct mutations in the gene for tau have been shown to cause FTDP-17 in more than 50 different kindreds by multiple mechanisms, such as altering tau splicing, disrupting tau’s ability to bind and stabilize microtubules, and increasing fibrillization of tau. These abnormalities might in turn lead to impaired axonal transport and synaptic dysfunction, and eventually cause neuronal degeneration.
Although in certain diseases (such as FTDP-17) tau dysfunction alone is sufficient to induce neurodegeneration, the frequency with which tau pathology occurs in a wide variety of other neurodegenerative diseases has led to the hypothesis that tau plays a role in a final, common pathway leading to neuronal death or dysfunction, which can be activated by several types of initiating events.
Like Aß, tau can be measured in the CSF, and total tau levels are elevated in the CSF of AD patients. Most informative are studies of particular species of phosphorylated tau (i.e., P-tau 181, 199, and 231) which show a good correlation with the diagnosis of AD.11
Tau pathology can be seen relatively early in the disease course, and elevated CSF tau is seen in MCI patients.12 Since CSF tau might reflect tau released from degenerating neurons, CSF tau levels can possibly provide a useful biomarker for neuronal damage, and thus should be downstream of most disease-modifying therapeutic interventions.
While CSF tau alone is not likely to be an effective biomarker for AD pathology due to lack of specificity, CSF tau might be very useful in combination with measures of CSF Aß. Indeed, when combined with CSF Aß levels, CSF tau levels can be used to predict progression from MCI to AD.5
Although FDDNP has been shown to image both tau pathology and amyloid pathology,8 no tau specific human imaging agents have been reported. Such an agent would represent a significant advance, and would greatly compliment existing techniques for amyloid imaging.
Other promising biomarkers
Markers for activated microglia and astrocytes (e.g. IL-1 and S100B) are actively under investigation as biomarkers in the serum and the CSF.13
Biomarkers for AD show evidence of oxidative damage in the brain. Isoprostanes, a marker of lipid peroxidation) have been shown to be a useful biomarker for AD when measured in the CSF, plasma, and urine.
Cerebral glucose metabolism, as measured by FDG-PET imaging, shows a characteristic pattern of hypometabolism in AD, which correlates well with regions of the brain thought to be most severely affected by the disease.
FDG-PET shows good sensitivity but poorer specificity for diagnosis of AD, and may be quite useful for differentiating AD from FTD.16 FDG-PET might also have utility in predicting conversion from MCI to AD.
Brain structural changes
Brain atrophy is a cardinal feature of AD, and quantitative MRI-based measure of brain volume (whole brain and specific brain regions) show a higher rate of brain volume loss in AD patients than in controls.18
Indeed, patients with MCI patients who eventually convert to AD show higher rates of volume loss than stable MCI patients. More importantly, these measures might correlate with neuronal loss and disease progression19.
Conclusion
An AD biomarker that is useful for early and accurate diagnosis and for selecting patients for therapy would represent a major technical and scientific advance. A number of potential biomarkers have been investigated, the most promising of which focus on the primary pathological lesions of AD (plaques and tangles). The largest ongoing effort to characterize both imaging and soluble biomarkers in AD is the Alzheimer’s Disease NeuroImaging Initiative (ADNI), a five-year, $60 million project sponsored by the National Institutes of Health (NIH) with support from pharmaceutical industry donations. ADNI includes evaluation of MRI measures, FDG-PET, CSF biomarkers (including Aß and tau) and PIB-PET as biomarkers for AD.21
Among the many experimental approaches investigated to date, one of the most exciting to date is amyloid plaque imaging. While these ligands have provided a boon to AD research, the next challenge is successful development and commercialization of the 18F-labeled, plaque-imaging ligands for eventual widespread clinical application.
About the Author
As the founder of Avid Radiopharmaceuticals, Dr. Skovronsky has more than 20 peer-reviewed publications and two NIH funded grants on Alzheimer’s disease research. He has served as Scientific Director of High-Throughput Screening and Drug Discovery at the Center for Neurodegenerative Disease Research at the University of Pennsylvania.
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This article was published in Drug Discovery & Development magazine: Vol. 10, No. 10, October, 2007, pp. 18-22.
Filed Under: Drug Discovery