A Multi-Cohort Study of ApoE ɛ4 and Amyloid-β Effects on the Hippocampus in Alzheimer’s Disease

Abstract

The apolipoprotein E (APOE) gene has been consistently shown to modulate the risk of Alzheimer’s disease (AD). Here, using an AD and normal aging dataset primarily consisting of three AD multi-center studies (n = 1,781), we compared the effect of APOE and amyloid-β (Aβ) on baseline hippocampal volumes in AD patients, mild cognitive impairment (MCI) subjects, and healthy controls. A large sample of healthy adolescents (n = 1,387) was also used to compare hippocampal volumes between APOE groups. Subjects had undergone a magnetic resonance imaging (MRI) scan and APOE genotyping. Hippocampal volumes were processed using FreeSurfer. In the AD and normal aging dataset, hippocampal comparisons were performed in each APOE group and in ɛ4 carriers with positron emission tomography (PET) Aβ who were dichotomized (Aβ+/Aβ–) using previous cut-offs. We found a linear reduction in hippocampal volumes with ɛ4 carriers possessing the smallest volumes, ɛ3 carriers possessing intermediate volumes, and ɛ2 carriers possessing the largest volumes. Moreover, AD and MCI ɛ4 carriers possessed the smallest hippocampal volumes and control ɛ2 carriers possessed the largest hippocampal volumes. Subjects with both APOE ɛ4 and Aβ positivity had the lowest hippocampal volumes when compared to Aβ- ɛ4 carriers, suggesting a synergistic relationship between APOE ɛ4 and Aβ. However, we found no hippocampal volume differences between APOE groups in healthy 14-year-old adolescents. Our findings suggest that the strongest neuroanatomic effect of APOE ɛ4 on the hippocampus is observed in AD and groups most at risk of developing the disease, whereas hippocampi of old and young healthy individuals remain unaffected.

The IMAGEN study: a decade of imaging genetics in adolescents

“…We identified 103 relevant original papers including published abstracts. Among these papers, 12 manuscripts reported associations between genetic variations and brain volume [ 4 , 14 , 19 , 22 – 30 ] (Table 1 ). Furthermore, 16 manuscripts reported associations of genetic variation on functional brain activation elicited by the MID task [ 15 , 31 – 45 ]; 6 papers described functional brain activation elicited by the SST [ 16 , 18 , 46 – 49 ], and 4 papers showed functional brain activation elicited by the EF [ 50 – 53 ] (Table 2 ).…”

“…The other polymorphisms associated with brain volume at age 14 contribute to metabolic and endocrine function (APOE), cell cycle and apoptosis (BABAM1, FBXW8, HMGA2, DDR2, HRK, BCL2L1, HMGA2, and Efhd2), neurodevelopment (NR2F6, USHBP1, DCC, and FAT3), and neurotransmission (DLG2, CHR1, CNR1, and NPTN). The longitudinal design of the IMAGEN study will help to assess whether the effects of these genetic variations on brain volume are also age dependent [ 4 , 14 , 19 , 22 – 28 ].…”

Immune and Imaging Correlates of Mild Cognitive Impairment Conversion to Alzheimer’s Disease

“…We focused on imaging analyses of MRI-based measures of hippocampal volumes, one of the core diagnostic criteria for probable AD dementia 2 ; thus we verified whether this parameter could be used as a biomarker to assess the presence of downstream neuronal degeneration or injury. Notably, hippocampal volume was recently suggested to be a possibly adequate index for the screening of subjects at risk of developing AD 19 , 31 .…”

Monitoring disease progression in mild cognitive impairment: Associations between atrophy patterns, cognition, APOE and amyloid

“…Interestingly, within AD-like MCI subjects a faster increase of SI in ε4 + subjects compared to ε4 − subjects was observed, but not in CN-like MCI subjects. This suggests that the presence of the ε4 allele accelerates atrophy in subjects with positive disease biomarkers ( Khan et al, 2017 ).…”