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We show that Reelin and A\u03b2 oligomers co-immunoprecipitated in human brain extracts and were present in the same size-exclusion chromatography fractions. A\u03b2 treatment of cells led to increase expression of Reelin, but secreted Reelin results trapped together with A\u03b2 aggregates. In frontal cortex extracts an increase in Reelin mRNA and in soluble and insoluble (guanidine-extractable) Reelin protein, was associated with late Braak stages of Alzheimer\u2019s disease (AD), while expression of its receptor, ApoER2, did not change. However, Reelin-dependent induction of Dab1 phosphorylation appeared reduced in AD. In cells, A\u03b2 reduced the capacity of Reelin to induce internalization of biotinylated ApoER2 and ApoER2 processing. Soluble proteolytic fragments of ApoER2 generated after Reelin binding can be detected in cerebrospinal fluid (CSF). Quantification of these soluble fragments in CSF could be a tool to evaluate the efficiency of Reelin signaling in the brain. These CSF-ApoER2 fragments correlated with Reelin levels only in control subjects, not in AD, where these fragments diminished. 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