roup is similar to that in the amyloid-positive AD dementia group. On the other hand, the APOE ε4 frequency in amyloid-negative aMCI patients is similar to that in amyloid-negative normal subjects (Table [2](#T2){ref-type="table"}). Previous studies reported that there was a significant association of APOE ε4 allele and late-onset AD, and the APOE ε4 frequency was significantly higher in sporadic AD patients than in controls \[[@B38]\]. APOE ε4 is a very strong risk factor for AD in the cohort study and lowers age at onset of late-onset AD significantly \[[@B39]\]. The APOE ε4 allele is associated with the molecular pathway that promotes late-onset AD \[[@B40]\] and is a risk factor not only for late-onset AD, but also for early-onset AD \[[@B41]\]. Our results showed that the APOE ε4 allele also bears strong association with amyloidosis in preclinical AD and prodromal AD as well as AD dementia, and that it is a strong predictor of amyloidosis in patients with aMCI and preclinical AD. Our findings are important for ongoing and future clinical trials involving participants with prodromal AD.

Overall, cognitive performance on all tests did not distinguish prodromal AD from amyloid-negative aMCI in the aMCI group (online suppl. Table [1](#S1){ref-type="supplementary-material"}). This result suggests that Aβ depositions are not severe enough to affect cognitive function or are compensated by brain changes in patients with aMCI.

Conclusion {#sec1_5}
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When considering the sensitivity, specificity, reliability, costs, and invasiveness of different biomarkers, we propose that the described CSF biomarkers be used as a first-line choice for the differentiation of prodromal AD in clinically diagnosed aMCI patients or for selecting very early AD dementia to be treated with the new disease-modifying agents. Accordingly, the introduction of CSF examination as a routine diagnostic procedure for selecting prodromal AD should be considered in the net decisions of diagnostic guidelines for AD dementia. CSF biom