S2-01-01: Overview of biomarkers

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Early diagnosis of AD will be of utmost importance if disease-arresting drugs, such as Aβ 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 Aβ in plaques (the 42 amino acid form of Aβ, Aβ42), 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). Recently, standardized assays have also been developed to cover other aspects of the AD pathogenesis, including APP isoforms (sAPPα and sAPPβ), BACE1 activity and Aβ isoforms (Aβ42/Aβ40 ratio). These biomarkers are now being evaluated by several research groups. 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 Aβ isoforms in human CSF, we found a series of shorter isoforms, including Aβ1–15, Aβ1–16 and Aβ1–17. In the first clinical study showed an increase in Aβ1–16, apart from the expected decrease in Aβ1–42. The origin of these shorter Aβ isoforms is unclear, but further experiments show that they are not formed by proteolytic degradation of longer Aβ isoforms. Instead, they may represent a novel pathway for APP processing, the combined action of BACE1 and α-secretase. CSF biomarkers may also be valuable to identify and monitor the biochemical effect of new Aβ 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 Aβ42 and β-sAPP) of an Aβ 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 Aβ modulatory treatment. Data from recent clinical trials using CSF biomarkers will be presented.