We found that the baseline levels of CSF tau were increased with around 60% in AD patients compared to controls, while baseline CSF Aβ42 levels were decreased with more than 50%. In AD patients, tau increased with 16% over two years and CSF tau was moderately associated with worse cognitive performance already at baseline. However, the levels of tau were stable over 4 years in the controls. The levels of Aβ42 did not change significantly over time in any of the groups and did not correlate with baseline cognitive performance.
Biomarkers for neurodegenerative disorders can be divided into markers of disease state and markers of disease stage or rate
. Markers of disease state, usually called diagnostic biomarkers, facilitate detection of a certain biological disease in populations of individuals with similar symptoms (e.g. memory impairment) caused by different conditions. A disease state marker should ideally exhibit a high diagnostic accuracy over the entire course of the disease process. Both CSF tau and Aβ42 fulfill the requirements for disease state markers of AD, because these biomarkers exhibit reasonably high specificity and sensitivity for both early and late stages of AD
. The results of the present study suggest that CSF Aβ42 is not a marker of disease stage or rate, since the levels are stable over time in individual patients with AD and do not correlate with cognitive function. Similarly, previous studies show that the amyloid load in the brain of AD patients, as assessed with repeated positron emission tomography (PIB-PET) measurements, keeps stable over time despite cognitive decline
. It might be that Aβ42 levels in both the CSF and the brain are altered during the very early preclinical stages of AD and are thereafter relatively stable during the symptomatic course of the disease.
The present study suggests that tau levels in CSF increase slightly over time. In agreement, Stefani and collaborators have found that CSF tau levels are associated with the disease stage of AD
, a finding supported by the moderate correlation between cognitive performance and CSF tau found in the present study. Therefore, it might be that CSF tau, in addition to being a robust disease state marker, to some degree reflects the disease stage. These observations are supported by neuropathological studies showing that tau-containing neurofibrillary tangles, but not amyloid plaques, are associated with the cognitive function of AD patients
. However, other methods such as cognitive tests or measures of brain atrophy or cerebral blood flow are likely to prove to be more valuable as disease stage markers of AD
, and CSF biomarkers should primarily be used as diagnostic markers detecting the underlying disease state
. Therefore, different methods should be combined when defining the disease state and stage of individual patients with cognitive dysfunction.
CSF biomarkers, such as tau and Aβ42, could possibly also be used as surrogate markers
in clinical therapeutic AD trials. Surrogate biomarkers should be involved in the early pathophysiologic cascade and they ought to inform on biological interactions with the molecular target of the drug in humans 
. Future disease-modifying therapies against AD may halt the degenerative process, but are not expected to have direct symptomatic effects. As a result no short-term cognitive improvements are expected in such trials. Therefore, large patient populations and extensive treatment periods will be required to identify treatment effects on clinical parameters. Data from smaller pilot investigations, using biomarkers as endpoint to determine whether a certain drug is reaching and acting on its biological target in patients with AD, would be very valuable when making a go/no-go decision for an expensive clinical trial with clinical improvement as the endpoint
. However, the markers used as surrogate markers in such trials must have a low intra-individual variation over time. The present study confirms previous investigations that the changes of CSF tau and Aβ42 is very modest over time in individual patients with AD
, which might indicate that these CSF biomarkers may serve as sensitive tools to identify and monitor even minor biochemical changes induced by treatments that are directed against these targets, such as Aβ immunotherapy. For example, recently Lannfelt and colleagues found that PBT2 (a metal-protein attenuating compound) reduced the levels of Aβ42 in CSF, but not plasma, of patients with AD, indicating that the drug had a central effect on Aβ metabolism
In conclusion, CSF tau and Aβ42 seem to reflect the underlying disease state in both early and late stages of AD. The slight increase in tau over time observed in patients with AD is modest when compared to the relatively large difference in absolute tau levels observed between AD patients and controls, indicating that tau and Aβ42 do not primarily reflect the progression of the disease over time. Therefore, these markers might serve as surrogate markers for treatment efficacy in clinical trials.