Cerebrospinal fluid (CSF) amyloid beta42 (Abeta42) concentrations are decreased in patients with Alzheimer disease (AD). Consequently, low Abeta42 is considered a positive biomarker for AD. Surprisingly, the mechanisms that underlie the decrease in CSF Abeta42 remain speculative. Better understanding of this biomarker is an essential step to unravel AD pathophysiology and to develop and evaluate treatment. Therefore, we systematically examined the possible reasons for the decreased CSF Abeta42 concentration in AD. Under normal conditions, Abeta42 can be degraded by proteases, taken up by microglia, or cleared from the brain interstitial fluid across the blood brain barrier. Alternatively, it can be transported to the CSF and be cleared from there. Aggregation of Abeta42 appears the most likely cause for the decreased CSF Abeta42 concentration in AD: the aggregated state inhibits Abeta42 from being transported from the ISF to the CSF. Evidence for other possibilities such as a decreased production of Abeta42, an increased proteolytic breakdown or microglial uptake of Abeta42, or an increased clearance of Abeta42 to the blood, is - at best - scarce or even absent.