Interactive effect of age and APOE-ε4 allele load on white matter myelin content in cognitively normal middle-aged subjects

Abstract

The apolipoprotein E gene (APOE) ε4 allele has a strong and manifold impact on cognition and neuroimaging phenotypes in cognitively normal subjects, including alterations in the white matter (WM) microstructure. Such alterations have often been regarded as a reflection of potential thinning of the myelin sheath along axons, rather than pure axonal degeneration. Considering the main role of APOE in brain lipid transport, characterizing the impact of APOE on the myelin coating is therefore of crucial interest, especially in healthy APOE-ε4 homozygous individuals, who are exposed to a twelve-fold higher risk of developing Alzheimer's disease (AD), compared to the rest of the population.We examined T1w/T2w ratio maps in 515 cognitively healthy middle-aged participants from the ALFA study (ALzheimer and FAmilies) cohort, a single-site population-based study enriched for AD risk (68 APOE-ε4 homozygotes, 197 heterozygotes, and 250 non-carriers). Using tract-based spatial statistics, we assessed the impact of age and APOE genotype on this ratio taken as an indirect descriptor of myelin content.Healthy APOE-ε4 carriers display decreased T1w/T2w ratios in extensive regions in a dose-dependent manner. These differences were found to interact with age, suggesting faster changes in individuals with more ε4 alleles.These results obtained with T1w/T2w ratios, confirm the increased vulnerability of WM tracts in APOE-ε4 healthy carriers. Early alterations of myelin content could be the result of the impaired function of the ε4 isoform of the APOE protein in cholesterol transport. These findings help to clarify the possible interactions between the APOE-dependent non-pathological burden and age-related changes potentially at the source of the AD pathological cascade.

Signature of Alzheimer’s Disease in Intestinal Microbiome: Results From the AlzBiom Study

“…The procedure for determining the apolipoprotein (ApoE) genotype was performed as previously described ( Operto et al, 2019 ). Briefly, total DNA was obtained from the blood cellular fraction by proteinase K digestion followed by alcohol precipitation, using the QIAamp DNA Blood Maxi Kit.…”

Empirical Transmit Field Bias Correction of T1w/T2w Myelin Maps

“…For this reason, Voxel Based Morphometry (VBM) style analyses are never appropriate in T1w/T2w studies of the cerebral cortex. Skeletonized methods such as Tract-Based-Spatial-Statistics (TBSS; Smith et al, 2006) offer the best option for voxelwise white matter analysis (e.g., Operto et al, 2019), though tractography-based tract analyses would likely be even better (Chen et al, 2017; Thompson et al, 2020).…”

“…Importantly, however, it is NOT appropriate to attempt "VBMstyle" analyses of these T1w/T2w ratio volumes in lieu of proper surface-based cortical analyses for reasons described elsewhere (Glasser et al, 2016b;Coalson et al, 2018), and also because partial volume effects of CSF, grey matter, and white matter will completely dominate the differential effects of myelin content in traditional volume-based analyses (i.e., the differences in T1w/T2w ratio between tissues are much larger than those within tissues). Skeletonized methods such as Tract-Based-Spatial-Statistics (TBSS; Smith et al, 2006) offer the best option for voxelwise white matter analysis (e.g., Operto et al, 2019), though tractography-based tract analyses would likely be even better (Chen et al, 2017;Thompson et al, 2020).…”

APOE ε4 allele accelerates age-related multi-cognitive decline and white matter damage in non-demented elderly

“…Therefore, identifying joint contribution of APOE ε4 allele and age on the brain and cognition could have a profound impact on our understanding of the underlying process that influences brain function in disease. Operto et al found a significant negative interaction between the number of APOE ε4 alelles and age in extensive bilateral regions of the WM in both the recessive and the additive contrast [19]. However, does the APOE ε4 allele moderate agerelated changes in WM fibers integrity?…”