DOES APOE-ε4 HAVE AN Aβ-INDEPENDENT EFFECT ON TAU PATHOLOGY? NEUROIMAGING INVESTIGATIONS IN COGNITIVELY NORMAL ELDERS AND PATIENTS WITH ALZHEIMER’S DISEASE

Abstract

The apolipoprotein E (APOE) ε4 allele is associated with an increase in Aβ pathology; yet, ε4 is suspected to have additional Aβ-independent effects on AD pathophysiology. Here, we aimed to assess potential Aβ-independent effects of ε4 on tau pathology using PET imaging with [18F]AV1451 and [11C]PIB. Two cohorts were studied: i) a group of 71 cognitively normal elders, ii) a group of 44 clinically impaired PIB-positive patients (patients with MCI or at the dementia stage), see Table 1 for demographics. PET data were processed using Freesurfer 5.3 and SPM12 to compute Standardized Uptake Value Ratio (SUVR) images normalized to cerebellar gray matter (PIB and AV1451). Statistical analyses were performed separately in the two cohorts, assessing both ε4-related differences on global cortical uptake and conducting voxelwise analyses. In the whole cognitively normal group, ε4 was associated with higher cortical PIB but not AV1451-SUVR (Fig 1a). Voxelwise analyses showed that ε4 was associated with higher PIB-SUVR in the entire cortex (Fig 1b). AV1451-uptake was increased in ε4 carriers in the temporal lobe, but this effect was not significant after controlling for PIB status or SUVR (Fig 1c). In patients, the presence of the ε4 allele was not associated with significant differences in global measures of AV1451 or PIB-SUVR (Fig 2a). Voxelwise analyses showed no difference on PIB-PET, while ε4 carriers had higher AV1451-uptake in the anterior medial temporal lobe (MTL); that difference remained unchanged when controlling for PIB-SUVR (Fig 2b). In ε4-carriers, AV1451-uptake in the MTL was associated with lower performances in delayed recall, but not other cognitive tests (Fig 2c). In cognitively normal individuals, the effect of APOE ε4 on tau pathology seems to be driven by the effect of ε4 on Aβ deposition. However, when assessing amyloid-positive symptomatic AD patients, ε4 was associated with increased AV1451 binding in the MTL. This suggests that, in addition to its effect of Aβ pathology, ε4 might influence the topographical distribution of tau pathology, and potentially the cognitive symptoms in patients. Effect of ε4 in cognitively normal individuals. Effect of ε4 in cognitively impaired PIB-positive patients.