APOLIPOPROTEIN E AND BIN1 POLYMORPHISMS DIFFERENTIALLY AFFECT CORTICAL AMYLOID AND TAU LOAD IN HEALTHY OLDER ADULTS

Abstract

Genome-wide association studies have revealed multiple risk polymorphisms for Alzheimer's disease (AD). Some, like APOE, are well-known to be associated with the amyloidogenic pathway according to numerous amyloid PET studies. Others, like Bridging Integrator 1 (BIN1), are hypothesized to mediate genetic risk for AD by modulating tau pathology based on preclinical evidence as well as postmortem studies in AD (Chapuis et al, 2013). Here we examined in cognitively intact older adults whether APOE and BIN1 exert differential effects on amyloid and tau load using [11]C-PIB and [18]F-AV1451 PET, respectively. 40 community-recruited healthy individuals (age 72.4±5.6, 17 men/23 women) who were cognitively intact participated. Subjects were stratified at inclusion for the APOE4 carrier status. Twenty-one were carriers of the APOE4 allele (two APOE4 homozygotes). Nineteen were carriers of the BIN1 rs744373 risk polymorphism (two G/G homozygotes). All participants underwent a 60 minutes dynamic [11]C-PIB and a 100 minutes dynamic [18]F-AV1451 PET scan. [11]C-PIB and [18]F-AV1451 PET images were entered in a Logan graphical analysis with cerebellar GM as reference region to obtain Distribution Volume Ratios (DVR). Using whole-brain voxelwise analysis in SPM12, the [11]C-PIB and [18]F-AV1451 scans were compared between groups: APOE4 carriers versus noncarriers, BIN1 carriers versus noncarriers. Statistical significance threshold was set a whole-brain corrected cluster-level p<0.05. BIN1 risk allele carriers had higher [18]F-AV1451 binding in the prefrontal cortex (26, 62, 7, Z = 4.68, extent 641, corr. P = 0.045) than noncarriers. No differences were present in [11]C-PIB binding in BIN1 risk allele carriers versus noncarriers. APOE4 carriers had trend-level higher [11]C-PIB binding in frontal cortex compared to noncarriers (38, 38, -14, Z = 3.95, extent 258, corr. P = 0.050). APOE4 noncarriers in contrast had higher [18]F-AV1451 binding in distributed cortical regions compared to carriers (clusters 1 = -10, -82, 27, Z = 4.73, extent = 3580, corr. P = 0.000; cluster 2 = -38, -24, 23, Z = 4.01, extent = 1042, corr. P = 0.009). Our findings fit with a multidimensional model of AD where different risk factors may partly independently modulate the amyloidogenic and the tau aggregation pathway.