Impact of the APOE gene on amyloid deposition in participants with abnormal soluble amyloid levels

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AbstractBackgroundAmyloid pathology can be quantified both in the cerebro‐spinal fluid (CSF) and in positron emission tomography (PET) images, even though they measure two distinct amyloid pools. While CSF Aβ reflects the clearance of soluble amyloid species from the brain, PET imaging informs on the presence of insoluble fibrillary plaques. Many studies have shown the concordance of the two measures in individuals along the Alzheimer’s disease (AD) continuum. Here, we assessed whether APOE‐ε4, the major genetic risk factor for AD, affects the pattern of cerebral Aβ‐load as a function of CSF Aβ levels.MethodThe first consecutive 276 cognitively unimpaired (CDR=0) individuals of the ALFA+ study, aged between 48 and 74, with valid structural MRI and [18F]Flutemetamol (FTM) PET, APOE genotyping and CSF samples were included. Aβ‐40 and Aβ‐42 concentrations were determined with the NeuroToolKit (Roche Diagnostics International Ltd.) on a Elecsys cobas e‐411 instrument and parametric standardized uptake value ratio images (SUVr) were calculated with the whole cerebellum as reference region. A voxelwise regression to predict FTM uptake was performed, with the following independent variables: Age, Sex, APOE‐ε4, and CSF Aβ‐42/40. Statistical threshold was set to p<0.001 with a cluster extent correction of 100 voxels.ResultAs expected, CSF Aβ‐42/40 was strongly and negatively associated to cerebral FTM uptake (Fig. 1a‐1b). Age and APOE‐ε4 gene dose mapped onto distinct spatial patterns of FTM binding across the whole sample (Fig. 2b‐2c). Importantly, we found a significant interaction between Aβ‐42/40 and APOE‐ε4 indicating that carriers had a negative association between fluid and imaging Aβ measures in the bilateral hippocampus, as well as the bilateral middle temporal and temporo‐parietal junction (Fig. 3).ConclusionCompared to non‐carriers, APOE‐ε4 carriers show higher cerebral amyloid load for any given level of CSF Aβ 42/40 in areas which are not typically vulnerable to Aβ deposition yet undergoing neurodegeneration early in the AD continuum, such as the hippocampus. This suggests that APOE‐ε4 may influence the biological mechanisms regulating the equilibrium between soluble and deposited amyloid, which may transcend the hindering effect caused by Aβ fibrillary plaques and render medial temporal lobe structures particularly vulnerable when Aβ metabolism becomes deficient.