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Reddy MM, Wilson R, Wilson J, Connell S, Gocke A, Hynan L, German D, Kodadek T. Identification of candidate IgG biomarkers for Alzheimer's disease via combinatorial library screening. Cell. 2011 Jan 7;144(1):132-42. PubMed.
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I think this new unbiased technology of looking for IgGs that bind to unique shapes on synthetic peptoids provides a valuable new methodology for discovery of IgGs that may be specific for certain disease states. The authors provide a good proof-of-concept experiment in experimental autoimmune encephalomyelitis (mouse model of multiple sclerosis), and also show that, in a small set of Alzheimer’s disease cases and controls, this approach can identify unique IgGs that are present in AD. They validated their initial finding from N = 6 AD cases and N = 6 controls and in an additional group of N = 16 AD, N = 16 controls and N = 6 lupus patients with sensitivity and specificity greater than 90 percent. While the numbers are small, the data clearly show the promise of this technique in the potential development of a serum biomarker, but also in identifying the unique antigen that these antibodies bind to. If this can be done on a much larger number of samples in which a lot more biomarker information is known (CSF, amyloid imaging, etc.), this has the potential to be a big advance in the AD biomarker field. It may also be very useful for biomarker identification for other neurodegenerative and neurological disorders.
Stanford University Medical School
This report by Kodadek’s group describes a novel approach in the search for disease-specific molecular biomarkers. The authors are screening patient sera to find specific endogenous immunoglobulins that would be characteristic of a given disease. The rationale for the existence of such antibodies is based on the hypothesis that the patient mounts an immune response against disease-specific molecular species (or pathogens) with subsequent production of specific antibodies. There is no consistent evidence that this is the case for Alzheimer’s disease (AD) or other neurodegenerative diseases, but dozens of isolated studies in the literature have described antibodies with distinct antigen specificity that are overrepresented in AD compared with healthy controls.
The current study takes an unbiased approach to identify novel species of IgG immunoglobulins using a library of 15,000 peptoids, peptide-like small polymers that represent diverse molecular shapes but do not necessarily model native biological molecules. Using this approach, the team isolated three peptoids that captured IgGs in serum from AD patients with at least threefold higher binding activity than in serum from matched controls. This is promising and provides a potential new way to find subtle changes in the immune repertoire of AD patients. Similar to their proof-of-concept work in a mouse model of autoimmune neuroinflammation, it may be possible to identify the nature of the antigen recognized by the peptoid specific IgGs in AD patients.
The utility as a biomarker test for AD, however, may be a long way off, as many of the aforementioned studies have shown (or rather failed to show). The number of samples used in the current study was very small, and it remains to be shown how the test would perform if another 1,000 samples were measured. The good news is that large AD plasma sample collections exist now (e.g., the Alzheimer’s Disease Neuroimaging Initiative or the Australian Imaging Biomarker and Lifestyle Flagship Study of Ageing), and the specificity of the test could be validated relatively quickly. It is also unclear how many peptoids were identified to be significantly different between disease and control. Three out of 15,000 would be an extremely small number to identify with convincing statistical power using current algorithms, but maybe many hundreds of additional peptoids with detectable but lower binding capacity were found. On the other hand, the small number of peptoids could indicate that AD patients possess a highly specific immune response against an unknown antigen. If true, that would most certainly change the current view of this disease.
In summary, the current study describes an exciting new tool to rapidly probe the immune repertoire of humans and other species. This could lead to the discovery of new antigens and pathological processes involved in disease and possibly to the development of new biomarkers.
This is good work. The biomarker is the most important tool for studying AD. The authors report results for a small number of patients for whom diagnosis was confirmed at autopsy. It is also very important to diagnose in living subjects who have early AD or MCI. In addition to AD biomarkers, one should also focus on tau, which is another hallmark of AD. AD biomarkers are valuable in different ways. The important factor is to identify the people, or groups, who have greater risk to develop AD.
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