Cerebrospinal fluid biomarkers for Alzheimer's disease: current limitations and recent developments

To give perspectives on current limitations and recent developments in the field of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD).

Three CSF biomarkers for the neuropathological hallmarks of Alzheimer's disease, namely total tau (T-tau), phospho-tau (P-tau) and the 42 amino acid form of amyloid β (Aβ42), reflecting neurodegeneration, neurofibrillary tangles and amyloid/senile plaques, respectively, have been developed, validated and incorporated into new diagnostic criteria for the disease. Thanks to global collaborative research efforts, these have been to a large extent a success story but there are a number of limitations that warrant further research and discussion. First, bias and random variation in biomarker measurements both within and between laboratories remain an issue. Second, current markers only reflect part of the pathology underlying Alzheimer's disease; new markers of synaptic dysfunction, microglial activation and protein aggregates that are frequently seen alongside plaque and tangle pathology are needed. Third, fluid markers do not represent the anatomic location of any pathological change; CSF markers may be complemented with high resolution molecular imaging techniques.

There has been considerable progress in the validation and standardization of assays for CSF T-tau, P-tau and Aβ42. Novel biomarkers for synaptic function, microglial activation and protein accumulations other than tau and Aβ are in development. Future fluid biomarker research should be conducted in close collaboration with molecular imaging specialists.