White matter integrity and its association with amyloid-PET and serum NfL in healthyAPOE4homozygotes, heterozygotes and non-carries

AbstractExcept for aging,APOE ε4allele (APOE4) is the most important risk factor for sporadic Alzheimer’s disease.APOE4carriers may have reduced capacity to recycle lipids, resulting in reduced white matter integrity. Here, we evaluated if white matter impairment measured by diffusion tensor imaging (DTI) differs between healthy individuals with different number ofAPOE4alleles and if white matter impairment associates with brain beta-amyloid (Aβ) load and serum levels of neurofilament light chain (NfL). We studied 96 participants (APOE4/4,N= 20;APOE4/3,N= 39;APOE3/3,N= 37; mean age 70.7 (SD 5.22) years, 63% females) with brain MRI including a DTI sequence (N = 96), Aβ-PET (N = 89) and a venous blood sample for serum NfL concentration measurement (N = 88). Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AxD) in sixa priori-selected white matter regions-of-interest (ROIs) were compared between the groups using ANCOVA, with sex and age as covariates. A voxel-weighted average of FA, MD, RD and AxD was calculated for each subject, and correlations with Aβ-PET and NfL levels were evaluated.APOE4/4carriers exhibited higher MD and higher RD in the body of corpus callosum thanAPOE4/3(p = 0.0053 and p = 0.0049, respectively) andAPOE3/3(p = 0.026 and p = 0.042).APOE4/4carriers had higher AxD thanAPOE4/3(p = 0.012) andAPOE3/3(p = 0.040) in the right cingulum adjacent to cingulate cortex. In the total sample, composite MD, RD and AxD positively correlated with cortical Aβ load (r = 0.26 to 0.33, p < 0.013 for all) and with serum NfL concentrations (r = 0.31 to 0.36, p < 0.0028 for all). In conclusion, reduced white matter integrity was detected in cognitively unimpairedAPOE4/4homozygotes compared toAPOE4/3andAPOE3/3carriers and reduced white matter integrity correlated with biomarkers of Alzheimer’s disease and neurodegeneration. White matter impairment seems to be an early phenomenon in the Alzheimer’s disease pathologic process inAPOE4/4homozygotes.HighlightsCognitively normal elderlyAPOE4homozygotes showed impaired white matter integrityAPOE4homozygotes showed higher diffusivity in corpus callosum and right cingulumMD, RD and AxD correlate with amyloid load assessed by PET inAPOE4carriersMD, RD and AxD correlate with serum neurofilament light chain inAPOE4carriersWhite matter impairment may be an early phenomenon in the AD pathologic process