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Cerebral beta-amyloid (Aβ) accumulation is the earliest detectable pathophysiological event along the Alzheimer’s disease (AD) continuum, therefore an accurate quantification of incipient Aβ abnormality is of great importance to identify preclinical AD. Both cerebrospinal fluid (CSF) Aβ concentrations and Position Emission Tomography (PET) with specific tracers provide established biomarkers of Aβ pathology. Yet, they identify two different biological processes reflecting the clearance rate of soluble Aβ as opposed to the cerebral aggregation of insoluble Aβ fibrils. Studies have demonstrated high agreement between CSF and PET-based Aβ measurements on diagnostic and prognostic levels. However, an open question is whether risk factors known to increase AD prevalence may promote an imbalance between these biomarkers, leading to a higher cumulative Aβ cerebral aggregation for a given level of cleared Aβ in the CSF. Unveiling such interactions in cognitively unimpaired (CU) individuals shall provide novel insights into the biological pathways underlying Aβ aggregation in the brain and ultimately improve our knowledge on disease modelling. With this in mind, we assessed the impact of three major unmodifiable AD risk factors (age, APOE-ε4 and sex) on the association between soluble and deposited Aβ in a sample of 293 middle-aged CU individuals who underwent both lumbar puncture and PET imaging using the [18F]flutemetamol tracer. We looked for interactions between CSF Aβ42/40 concentrations and each of the assessed risk factors, in promoting Aβ PET uptake both in candidate regions of interest and in the whole brain. We found that, for any given level of CSF Aβ42/40, older age and female sex induced higher fibrillary plaque deposition in neocortical areas including the anterior, middle and posterior cingulate cortex. By contrast, the modulatory role of APOE-ε4 was uniquely prominent in areas known for being vulnerable to early tau deposition, such as the entorhinal cortex and the hippocampus bilaterally. Post hoc three-way interactions additionally proved evidence for a synergistic effect among the risk factors on the spatial topology of Aβ deposition as a function of CSF Aβ4/40 levels. Importantly, findings were replicated in an independent sample of CU individuals derived from the ADNI cohort. Our data clarify the mechanisms underlying the higher AD prevalence associated to those risk factors and suggest that APOE-ε4 in particular paves the way for subsequent tau spreading in the medial temporal lobe, thus favoring a spatial co-localization between Aβ and tau and increasing their synergistic interaction along the disease continuum.