Tract Based Spatial Statistic reveals in 1 microstructural organisation between carriers and non-carriers of the ApoE ε4 2 and ε2 alleles in young healthy adolescents 3

The Apolipoprotein E (ApoE) ε4 allele is the best established genetic risk factor for 52 Alzheimer’s disease (AD) and has been previously associated with alterations in 53 structural gray matter and changes in functional brain activity in healthy middle-aged 54 individuals and older non-demented subjects. In order to determine the neural 55 mechanism by which ApoE polymorphisms affect white matter (WM) structure, we 56 investigated the diffusion characteristics of white matter tracts in carriers and non- 57 carriers of the ApoE ε4 and ε2 alleles using an unbiased whole brain analysis 58 technique (Tract Based Spatial Statistics (TBSS)) in a healthy young adolescent 59 (14years) cohort. A large sample of healthy young adolescents (n=575) were 60 selected from the European neuroimaging-genetics IMAGEN study with available 61 ApoE status and accompanying diffusion imaging data. MR Diffusion data was 62 acquired on 3T systems using 32 diffusion-weighted (DW) directions and 4 non-DW 63 volumes (b-value = 1300 s/mm 2 and isotropic resolution of 2.4x2.4x2.4 mm). No 64 significant differences in WM structure were found in diffusion indices between 65 carriers and non-carriers of the ApoE ε4 and ε2 alleles, and dose-dependent effects 66 of these variants were not established, suggesting that differences in WM structure 67 are not modulated by the ApoE polymorphism. In conclusion, our results suggest 68 that microstructural properties of WM structure are not associated with the ApoE ε4 69 and ε2 alleles in young adolescence, suggesting that the neural effects of these 70 variants are not evident in 14-year olds and may only develop later in life.