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S2‐01–01: Overview of biomarkers
Author(s) -
Blennow Kaj
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.269
Subject(s) - gene isoform , immunoprecipitation , pathogenesis , phosphorylation , biomarker , proteomics , disease , dementia , tau protein , medicine , chemistry , cancer research , alzheimer's disease , bioinformatics , biology , biochemistry , immunology , antibody , gene
Background: Early diagnosis of AD will be of utmost importance if disease-arresting drugs, such as A immunotherapy, prove to be effective. CSF biomarkers reflect the central pathogenic processes in AD, including the neuronal degeneration (total tau, T-tau), the deposition of A in plaques (the 42 amino acid form of A , A 42), and the phosphorylation of tau with formation of tangles (phospho tau, P-tau). These biomarkers have consistently been found to have high diagnostic accuracy for AD and for MCI cases that will progress to AD with dementia (i.e. have incipient AD). Methods: Recently, standardized assays have also been developed to cover other aspects of the AD pathogenesis, including APP isoforms (sAPP and sAPP ), BACE1 activity and A isoforms (A 42/A 40 ratio). These biomarkers are now being evaluated by several research groups. Results: There is also an ongoing search for new CSF biomarkers for AD using proteomics techniques. Using a combination of immunoprecipitation (IP) and mass spectrometry (MALDI-TOF-MS and FT-ICR-MS) to identify novel A isoforms in human CSF, we found a series of shorter isoforms, including A 1-15, A 1-16 and A 1-17. In the first clinical study showed an increase in A 1-16, apart from the expected decrease in A 1-42. The origin of these shorter A isoforms is unclear, but further experiments show that they are not formed by proteolytic degradation of longer A isoforms. Instead, they may represent a novel pathway for APP processing, the combined action of BACE1 and -secretase. Conclusions: CSF biomarkers may also be valuable to identify and monitor the biochemical effect of new A modulatory drug candidates directly in living AD patients. In this context, a primary (or “specific”) biomarker is designed to monitor the central biochemical effect (such as A 42 and -sAPP) of an A modulatory drug, while a secondary (or “downstream”) biomarker (such as T-tau) monitor downstream effects such the neuronal degeneration. The intra-individual variation of these CSF biomarkers is remarkably low both during 6 and 24 months, suggesting that they have the potential to identify very minor biochemical changes induced by A modulatory treatment. Data from recent clinical trials using CSF biomarkers will be presented.