EXPLORING APOE GENOTYPE EFFECTS ON AD RISK AND BETA-AMYLOID BURDEN IN INDIVIDUALS WITH SUBJECTIVE COGNITIVE DECLINE: THE FACEHBI STUDY RESULTS

Abstract

Subjective cognitive decline (SCD) has been proposed as a potential preclinical stage of AD. Nevertheless, the genetic and biomarker profile of SCD individuals remains mostly unexplored. APOE Ɛ4 has been the unique locus associated with SCD and studies with amyloid biomarkers have showed inconsistent results. The integration of a multimodal approach, i.e. the combination of APOE status with cerebral amyloid burden could be useful to improve the discrimination of converters to AD. Here, we assessed the role of APOE Ɛ4 and Ɛ2 in the amyloid burden of 200 SCD individuals recruited in the FACEHBI study. A sample of 200 subjects with SCD was screened for brain amyloidosis using the [18F] Florbetaben Positron Emission Tomography (FBB-PET). To estimate the SCD phenotype as a risk factor of AD, we also used: 3,032 population based-controls, 1,170 MCI subjects and 2,517 AD patients. Crude and adjusted studies were performed using Plink software. Univariate analysis of variance was used to explore differential cerebral amyloid burden between carriers and non-carriers of APOE-Ɛ4 and Ɛ2. Linear regression model was applied to investigate the correlation between APOE allele dosage and FBB-PET. Statistical analyses and Meta-analysis were performed using SPSS and OpenMeta, respectively. In case of heterogeneity between studies, DerSimonian and Liard method was used. We found a significant association between APOE Ɛ4 and SCD diagnosis [OR=1.61(1.21 − 2.16); p=0.001]. Meta-analysis of the present results with prior studies (n=9,567), identified heterogeneity in the APOE Ɛ4 effect among series (I2=53%, p=0.03), reaching nominal statistical significance [OR=1.23 (1.01 − 1.51]; p=0.05]. In addition, SCD individuals carriers of APOE-Ɛ4 presented higher risk to suffer AD than non-carriers [OR=1.95(1.47 − 2.60); p=2.69e-06]. Furthermore, significant differences were found in cerebral amyloid burden between carriers and non-carriers of APOE-Ɛ4 (p=1.62e-05). However, APOE allele dosage only explained 9% of FBB-PET levels variation. Our study points out to the existence of a preclinical AD subgroup within the SCD population. We proposed that the variation in cerebral amyloid levels is partially explained by the APOE allele dosage, suggesting that other genetic or epigenetic factors are involved in this trait.