In vivo gold standard for the ante-mortem assessment of brain β-amyloid pathology is currently β-amyloid PET or cerebrospinal fluid measures of β-amyloid42 or the β-amyloid42/β-amyloid40 ratio. The widespread acceptance of a biomarker classification scheme for the Alzheimer’s disease continuum has ignited interest in more affordable and accessible approaches to detect Alzheimer’s disease β-amyloid pathology, a process that often slows down the recruitment into, and adds to the cost of, clinical trials. Recently there has been considerable excitement concerning the value of blood biomarkers. Leveraging multidisciplinary data from cognitively unimpaired participants and participants with mild cognitive impairment recruited by the multisite biomarker study of Alzheimer’s Disease Neuroimaging Initiative, here we assessed to what extent plasma β-amyloid42/β-amyloid40, neurofilament light, and phosphorylated-tau at threonine-181 biomarkers detect presence of β-amyloid pathology, and to what extent the addition of clinical information such as demographic data, APOE genotype, cognitive assessments, and MRI can assist plasma biomarkers in detecting β-amyloid-positivity. Our results confirm plasma β-amyloid42/β-amyloid40 as a robust biomarker of brain β-amyloid-positivity (area under curve of 0.80–0.87). Plasma phosphorylated-tau at threonine-181 detected β-amyloid-positivity only in the cognitive impaired with a moderate area under curve of 0.67, while plasma neurofilament light did not detect β-amyloid-positivity in either group of participants. Clinical information as well as MRI–score independently detected PET β-amyloid-positivity both in cognitive unimpaired and impaired (area under curve of 0.69–0.81). Clinical information, particularly APOE ε4 status, enhanced performance of plasma biomarkers in the detection of PET β-amyloid-positivity by 0.06–0.14 units of area under curve for cognitive unimpaired, and by 0.21–0.25 units for cognitive impaired; and further enhancement of these models with an MRI–score of β-amyloid-positivity yielded an additional improvement of 0.04–0.11 units of area under curve for cognitive unimpaired and 0.05–0.09 units for cognitive impaired. Taken together, these multidisciplinary results suggest that when combined with clinical information, plasma phosphorylated-tau at threonine-181 and neurofilament light biomarkers, and an MRI–score could effectively identify β-amyloid+ cognitive unimpaired and impaired (area under curve of 0.80–0.90). Yet, when the MRI–score is considered in combination with clinical information, plasma phosphorylated-tau at threonine-181 and plasma neurofilament light have minimal added value for detecting β-amyloid-positivity. Our systematic comparison of β-amyloid-positivity detection models identified effective combinations of demographics, APOE, global cognition, MRI, and plasma biomarkers. Promising minimally invasive and low-cost predictors such as plasma biomarkers of β-amyloid42/β-amyloid40 may be improved by age and APOE genotype.