Abstract
The diagnostic guidelines of Alzheimer’s disease (AD) have recently been updated to include brain imaging and cerebrospinal fluid (CSF) biomarkers, with the aim of increasing the certainty of whether a patient has an ongoing AD neuropathologic process or not. The CSF biomarkers total tau (T-tau), hyperphosphorylated tau (P-tau) and the 42 amino acid isoform of amyloid β (Aβ42) reflect the core pathologic features of AD, which are neuronal loss, intracellular neurofibrillary tangles and extracellular senile plaques. Since the pathologic processes of AD start decades before the first symptoms, these biomarkers may provide means of early disease detection. The updated guidelines identify three different stages of AD: preclinical AD, mild cognitive impairment (MCI) due to AD and AD with dementia. In this review, we aim to summarize the CSF biomarker data available for each of these stages. We also review results from blood biomarker studies. In summary, the core AD CSF biomarkers have high diagnostic accuracy both for AD with dementia and to predict incipient AD (MCI due to AD). Longitudinal studies on healthy elderly and recent cross-sectional studies on patients with dominantly inherited AD mutations have also found biomarker changes in cognitively normal at-risk individuals. This will be important if disease-modifying treatment becomes available, given that treatment will probably be most effective early in the disease. An important prerequisite for this is trustworthy analyses. Since measurements vary between studies and laboratories, standardization of analytical as well as pre-analytical procedures will be essential. This process is already initiated. Apart from filling diagnostic roles, biomarkers may also be utilized for prognosis, disease progression, development of new treatments, monitoring treatment effects and for increasing the knowledge about pathologic processes coupled to the disease. Hence, the search for new biomarkers continues. Several candidate biomarkers have been found in CSF, and although biomarkers in blood have been harder to find, some recent studies have presented encouraging results. But before drawing any major conclusions, these results need to be verified in independent studies.
Highlights
The diagnosis of Alzheimer’s disease (AD) can only be made with certainty after a patient has deceased, by histological examination of brain tissue at autopsy or, rarely, following brain biopsy
In 1984, a working group established by the National Institute of Neurological and Communicative disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association created clinical diagnostic guidelines of probable AD [2], which were validated against neuropathological diagnosis with a sensitivity and specificity of around 80 and 70%, respectively [3]
The included cerebrospinal fluid (CSF) biomarkers are the total amount of tau (T-tau), which reflects the intensity of neuroaxonal degeneration, P-tau, which may correlate with tangle pathology, and the 42 amino acid isoform of amyloid β (Aβ) (Aβ42), which correlates inversely with plaque pathology [5]
Summary
The diagnosis of Alzheimer’s disease (AD) can only be made with certainty after a patient has deceased, by histological examination of brain tissue at autopsy or, rarely, following brain biopsy. One large study found that CSF levels of Aβ42, T-tau and P-tau among MCI patients could predict progression to AD with good accuracy after a median follow-up period of 5.2 years [28]. Studies that compared patients with MCI or dementia that had a pathologic core CSF AD biomarker profile with controls with a normal profile found that the former group had increased levels of sAPPα and sAPPβ, but there were large overlaps between the groups [83,84,85]. By measuring the levels of several plasma analytes simultaneously, found biomarker patterns that successfully differentiated AD patients from controls [123,124] or were associated with MCI or AD [125]. Several of these biomarkers have been associated with AD when measured in CSF
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