Abstract
Alzheimer’s disease is the most common cause of dementia. Over the last three decades, research has advanced dramatically and provided a detailed understanding of the molecular events underlying the pathogenesis of Alzheimer’s disease. In parallel, assays for the detection of biomarkers that reflect the typical Alzheimer’s disease-associated pathology have been developed and validated in myriads of clinical studies. Such biomarkers complement clinical diagnosis and improve diagnostic accuracy. The use of biomarkers will become even more important with the advent of disease-modifying therapies. Such therapies will likely be most beneficial when administered early in the disease course. Here, we summarise the development of the core Alzheimer’s disease cerebrospinal fluid biomarkers: amyloid-β and tau. We provide an overview of their role in cellular physiology and Alzheimer’s disease pathology, and embed their development as cerebrospinal fluid biomarkers into the historical context of Alzheimer’s disease research. Finally, we summarise recommendations for their use in clinical practice, and outline perspectives for novel cerebrospinal fluid candidate biomarkers.
Highlights
Alzheimer’s disease (AD) is the most common cause of dementia [1]
Are the abundant senile plaques, composed of amyloid-β (Aβ), and neurofibrillary tangles (NFTs), neuropil threads, and dystrophic neurites composed of hyperphosphorylated tau [6]
This is supported by findings from (1) autopsy studies showing that levels of Aβ42 in postmortem ventricular cerebrospinal fluid (CSF) negatively correlate with plaque load at autopsy [73]; (2) analysis of antemortem lumbar CSF, with low levels correlating with postmortem plaque load [74]; and (3) functional imaging studies in which cerebral Aβ load is directly visualised by positron emission tomography (PET) using Aβ ligands, such as the 11c-labelled Pittsburgh Compound B (11c PIB), with higher Aβ ligand binding correlating with lower CSF Aβ42 levels [11,64,75,76,77,78]
Summary
Alzheimer’s disease (AD) is the most common cause of dementia [1]. It is a slowly progressive neurodegenerative disorder with an insidious onset marked by prominent initial impairment of episodic memory [2]. Many pathogenic cascades leading to Aβ generation and aggregation have been unveiled, and mechanisms underlying erroneous tau protein homeostasis have been deciphered [8] These scientific advances have enabled the development of novel treatment strategies with disease-modifying potential. Treatments labelled as “disease-modifiers” must show a beneficial effect on clinical parameters and must affect the central disease pathology [11,12] These challenges have initiated a concerted search of the research community for biomarkers that adequately mirror core elements of the disease process, serve as diagnostic tools, especially for early diagnosis, and identify and monitor the biochemical effects of the respective drug candidate [11,13]. We discuss additional and novel CSF biomarkers reflecting pathological disease processes in AD
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