Parental history of AD Reduced FA in cingulum, tapetum, uncinate fasciculus, HC, and adjacent WM No main effect of APOE on WM, but interaction with family history where family history and ε4+ induced reduced FA
While no main effect of APOE was observed onDTI measures, parental history of AD was associated with reduced WM integrity in brain areas deteriorated in AD, which in turn interacted with APOE.
APOE ε4+ Significant atrophy in Bil temporal lobes, occipital lobes, retrosplenial, and posterior cingulate Highest GM reduction >20%: entorhinal cortex, anterior temporal pole, superior and middle temporal gyrus, ventral, and dorsal occipital cortex APOE ε4+ versus ε4− Global GM reduction comparable (RH: 14 versus 15%; LH: 16 versus 17%) ε4+ more atrophy in medial and lateral temporal lobes, and right occipital pole
After assessing the whole cortical mantle, greater susceptibility of the MTL area was found in APOEε4 carriers.
Additive model GM reduction in Bil MTL (HC, amygdala, parahippocampal gyrus), fusiform cortex, and orbitofrontal cortex Genotypic model Partially overlapping with additive, extending from posterior MTL to inferior lateral temporal cortex
Dose-dependent decrease in medial and anterior temporal lobe volume per allelic (ε4) load. Variable regional association indicating that APOE works differently on mechanisms of disease expression.
No significant differences between ε4+ and ε4− on MTL atrophy, WM HI
APOE does not modulate white and gray matter in AD. While APOE influences risk of AD it appears not to modulate pathological processes after diagnosis.
Case-control analysis identified APOE and a new risk gene TOMM40 at 10−6 (10−11 at a haplotype level between APOE & TOMM40 rs11556505) 25 SNPs were associated with QT HC, including APOE
APOE has an effect on brain atrophy independent from overrepresentation in AD. A novel risk gene, TOMM40, was found to be associated with AD.
Progressive APOEε4+ 1 year prior to diagnosis: GM atrophy in right temporal lobe, HC, insula 1 year FU: GM atrophy Bil HC, parietal, insula, caudate Stable APOEε4+ 1 year FU GM atrophy Bil insula, temporal lobe
APOEε4+ converters show early GM loss 1 year prior to diagnosis, and atrophy progresses in ε4+ converters to AD. However, some MTL atrophy is present in APOEε4+ nonconverters, reflecting nonlinear effects of APOE ε4.
While significant atrophy was seen within the MTL in APOE ε4+ carriers with progressive MCI, the presence of an ε4 allele did not predict conversion to AD.
Volumetry whole brain GWAS Freesurfer QT: 56 areas VBM QT: 86 areas
APOE rs 429358 (ε4 dependence) associated with whole brain Freesurfer (15 regions) and VBM (4) phenotypes at 10.6 significance TOMM40 rs2075650 associated with Freesurfer (5) at 10−7 significance Freesurfer phenotypes APOE associated with widespread phenotypes TOMM40 specifically associated with left and right hippocampi and left amygdala
While APOE is associated with widespread cortical AD-like changes, TOMM40 appears to be associated mainly with MTL phenotypes. Both APOE and TOMM40 were found among the top 5 SNPs in the GWAS.
Significant differences in ADC and FA with increasing age in frontal WM, lateral parietal WM, centrum semiovale, genu and splenium of CC, temporal stem WM These age-related differences in WM integrity were more prominent in ε4+
No group differences in total brain volume, GM volume, WM volume Cortical thickness ε4+ Thicker cortex in bilateral occipital and occipito temporal areas, right parahippocampal gyrus and frontal areas
Thicker cortex in APOE ε4+ was found in regions adjacent to those that show accelerated age-related decline, indicating that although well preserved now they may eventually show cortical thinning.
Age related cortical thickness ε4+ Both ε4+ and ε4− have age-related thinning in occipital and insula, but ε4+ also show thinning of MTL
APOE ε4 may accelerate thinning in areas that decline with aging (medial prefrontal, pericentral cortex) as well as areas susceptible to Aβ aggregation (occipitotemporal, temporal cortex).
APOE ε4+ showed steeper age-related decline in radial diffusivity in late myelinated regions frontal lobe and genu of the CC
Late myelinated frontal regions appear more susceptible to age-related breakdown in APOE ε4+ carriers. This leads to progressive disconnection of cerebral networks in ε4 carriers and is supportive of an anterior-posterior WM degeneration gradient.
Dose-dependent increase in TOMM40 poly-T length associated with reduced GM volume in ventral posterior cingulate and medial ventral precuneus
A subgroup of APOE ε3 carriers with long poly-T length of the TOMM40 gene show brain changes in areas associated with AD. This indicates independent influence of TOMM40.
ADC: Apparent diffusion coefficient; APOE: Apolipoprotein E; Bil: Bilateral; CC: Corpus Callosum; DTI: Diffusion Tensor Imaging; ERC: Entorhinal cortex; FA: Fractional Anisotropy; FU; Follow up; GWAS: Genome Wide Association Studies; GM: Gray matter; HC: Hippocampus; HI: Hyperintensities: LH: Left Hemisphere; MD: Mean Diffusivity; MTL: Medial Temporal Lobe; QT: Quantitative Trait; RH: Right hemisphere; SNP: Single Nucleotide Polymorphism (denoted rs); TOMM40: Translocase of outer mitochondrial membrane 40; WM: White matter.