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Neurodegenerative dementias constitute a broad group of diseases in which abnormally folded proteins accumulate in specific brain regions and result in tissue reactions that eventually cause neuronal dysfunction and degeneration. Depending on where in the brain this happens, symptoms appear which may be used to classify the disorders on clinical grounds. However, brain changes in neurodegenerative dementias start to accumulate many years prior to symptom onset and there is a poor correlation between the clinical picture and what pathology that is the most likely to cause it. Thus, novel drug candidates having disease‐modifying effects that is targeting the underlying pathology and changes the course of the disease needs to be defined using objective biomarker‐based measures since the clinical symptoms are often non‐specific and overlap between different disorders. Furthermore, the treatment should ideally be initiated as soon as symptoms are evident or when biomarkers confirm an underlying pathology (pre‐clinical phase of the disease) to reduce irreversible damage to, for example, neurons, synapses and axons. Clinical trials in the pre‐clinical phase bring a greater importance to biomarkers since by definition the clinical effects are difficult or slow to discern in a population that is not yet clinically affected. Here, we discuss neuropathological changes that may underlie neurodegenerative dementias, including how they can be detected and quantified using currently available biofluid‐based biomarkers and how more of them could be identified using targeted proteomics approaches. This article is part of the special issue "Proteomics". [ABSTRACT FROM AUTHOR]

A clinical diagnosis of Alzheimer's disease is currently made on the basis of results from cognitive tests in combination with medical history and general clinical evaluation, but the peptide amyloid-beta (Aβ) in cerebrospinal fluid ( CSF) is increasingly used as a biomarker for amyloid pathology in clinical trials and in recently proposed revised clinical criteria for Alzheimer's disease. Recent analytical developments have resulted in mass spectrometry ( MS) reference measurement procedures for absolute quantification of Aβ1-42 in CSF. The CSF Aβ1-42/Aβ1-40 ratio has been suggested to improve the detection of cerebral amyloid deposition, by compensating for inter-individual variations in total Aβ production. Our aim was to cross-validate the reference measurement procedure as well as the Aβ1-42/Aβ1-40 and Aβ1-42/Aβ1-38 ratios in CSF, measured by high-resolution MS, with the cortical level of Aβ fibrils as measured by amyloid (18F-flutemetamol) positron emission tomography ( PET). We included 100 non-demented patients with cognitive symptoms from the Swedish Bio FINDER study, all of whom had undergone both lumbar puncture and 18F-flutemetamol PET. Comparing CSF Aβ1-42 concentrations with 18F-flutemetamol PET showed high concordance with an area under the receiver operating characteristic curve of 0.85 and a sensitivity and specificity of 82% and 81%, respectively. The ratio of Aβ1-42/Aβ1-40 or Aβ1-42/Aβ1-38 significantly improved concordance with an area under the receiver operating characteristic curve of 0.95 and a sensitivity and specificity of 96% and 91%, respectively. These results show that the CSF Aβ1-42/Aβ1-40 and Aβ1-42/Aβ1-38 ratios using the described MS method are strongly associated with cortical Aβ fibrils measured by 18F-flutemetamol PET. [ABSTRACT FROM AUTHOR]