, sex and

Cerebral beta-amyloid (A  ) accumulation is the earliest detectable pathophysiological event along the Alzheimer’s disease (AD) continuum , therefore an accurate quantification of incipient A  abnormality is of great importance to identify preclinical AD. Both cerebrospinal fluid (CSF) A  concentrations and Position Emission Tomography (PET) with specific tracers provide established biomarkers of A  pathology. Yet, they identify two different biological processes reflecting the clearance rate of soluble A  as opposed to the cerebral aggregation of insoluble A  fibrils. Studies have demonstrated high agreement between CSF and PET-based A  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 A  cerebral aggregation for a given level of cleared A  in the CSF. Unveiling such interactions in cognitively unimpaired (CU) individuals shall provide novel insights into the biological pathways underlying A  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 -  4 and sex) on the association between soluble and deposited A  in a sample of 293 middle-aged CU individuals who underwent both lumbar puncture and PET imaging using the [ 18 F]flutemetamol tracer. We looked for interactions between CSF A  42/40 concentrations and each of the assessed risk factors, in promoting A  PET uptake both in candidate regions of interest and in the whole brain. We found that, for any given level of CSF A  42/40, 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 -  4 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 A  deposition as a function of CSF A  levels