Amyloid-β as a biomarker for Alzheimer’s disease: quantification methods in body fluids

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, characterized by neuronal impairment leading to dramatic changes in brain. Amyloid-β peptides and tau protein are the most promising biomarkers for AD. Cerebrospinal fluid and plasma are used to determine the concentration of these species. Since the pathological processes of AD start decades before the first symptoms, biomarkers may provide the possibility of early disease detection. The application of rapidly emerging technology, such as mass spectrometry, has opened new avenues to accelerate biomarker discovery, both for diagnostic as well as for prognostic purposes. This review summarizes AD biomarker studies with focus on amyloid-β peptides in biological fluids and their quantification with immunoassays as well as the latest mass spectrometry-based methods.

Keywords:

• Alzheimer’s disease
• amyloid-β
• biomarker
• cerebrospinal fluid
• mass spectrometry
• plasma

Financial & competing interests disclosure

The authors are supported by the Protein research Unit Ruhr within Europe (PURE) and ‘Validierung Marker-freier Imaging Verfahren und neu identifizierter Biomarker unter Nutzung des PURE Konsortiums’, both projects of the State Government North Rhine-Westphalia (Germany) and the European Joint Programme Neurodegenerative Disease Research (JPND project: BIOMARKAPD). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Amyloid plaques are found in postmortem Alzheimer’s disease (AD) patients’ brains and their major components are amyloid-β peptides (Aβ). Aβ is a key component of the biochemical process of AD pathogenesis; therefore, it is studied as biomarker for diagnosis.

• Cerebrospinal fluid (CSF) is in direct contact with the brain and it is the most meaningful source of biomarkers for neurodegeneration and also of Aβ peptide concentration monitoring. Due to difficulties and side effects of CSF drawn, plasma is used as body fluid for AD biomarker studies.

• Aβ peptides are notoriously hydrophobic, they bind to biomolecules and they are produced by several organs in human body; their presence in blood is related to several biological processes, therefore, their identification/quantification in plasma is challenging.

• Plasma Aβ does not correlate to AD diagnosis or progression but it might be useful to monitor amyloid response for disease progression in drug targeting studies or drug treatment.

• Aβ concentrations in AD and healthy control subjects measured by ELISA show huge inter-laboratory differences. Antibody masking, Aβ oligomerization and complex formation make ELISA measurements less reproducible in inter-laboratory studies. A quantification method able to give an accurate absolute concentration value is needed.

• Mass spectrometry-based methods (like selected reaction monitoring) seem to be the best alternative to ELISA, able to give a reproducible quantification.

• Low endogenous Aβ need an enrichment prior to mass spectrometry-based quantification; immunoprecipitation and solid phase extraction are the most used and promising techniques.

Notes