The relationship between APOE genotype and subcortical volume: A UK Biobank study (N=36,920)

• Published in: Alzheimer's & dementia Vol. 17; no. S4
• Main Authors: Muir, Alexandra M, Ching, Christopher, Santhalingam, Vigneshwaran, Abaryan, Zvart, Zhu, Alyssa H, Thomopoulos, Sophia I, Jahanshad, Neda, Thompson, Paul M
• Format: Journal Article
• Language: English
• Published: 01.12.2021
• ISSN: 1552-5260; 1552-5279
• DOI: 10.1002/alz.055650

Background Two copies of the apolipoprotein (APOE) ε4 allele is associated with approximately 10 to 20 times greater risk for late‐onset Alzheimer’s disease (AD)1,2,3, depending on genetic ancestry. Although reduced hippocampus and amygdala volumes are seen in ε4 carriers with mild cognitive impairment (MCI) and AD4,5, the relationship between genetic risk and brain structure in healthy older adults is unresolved. Here we mapped normative subcortical volume trajectories in a large sample of healthy adults and tested for the effects of APOE genotype. Method T1‐weighted images from 36,920 UK Biobank7,8 participants () were processed using FreeSurfer 7.1. Averaged thalamus, pallidum, hippocampus, amygdala, caudate, nucleus accumbens, and lateral ventricle volumes were calculated. APOE genotypes included ε2ε2, ε2ε3, ε3ε3, ε3ε4, and ε4ε4. ε2ε4 carriers and individuals with neurological/psychological disorders were not included. Nomograms of subcortical volumes were plotted. The statistical relationship between subcortical volume and APOE genotype was assessed using linear mixed models, adjusting for age, sex, intracranial volume, population structure, and scan site. Additionally, an age‐by‐APOE interaction was assessed, with all p‐values corrected using the standard false discovery rate9. Result Nomograms separated by APOE genotype () show a general trend of smaller volumes, but larger ventricles, with increasing age. Statistically, hippocampal and amygdala volumes were smaller in ε4ε4 compared to carriers of the ε3 allele (; d: ‐0.12 to ‐0.05). Carriers of at least one ε4 allele had smaller nucleus accumbens and thalamic volumes compared to carriers of the ε3 allele (d: ‐0.08 to ‐0.03). Lower thalamic volumes were associated with ε2ε2 compared to ε2ε3 and ε3ε3 (d: ‐0.14 to ‐0.03). No ROI showed a significant age‐by‐APOE genotype interaction. Conclusion These results suggest a pattern of subtle and structure‐specific effects of AD genetic risk on subcortical volume across adulthood. Future studies aim to bolster the ε2ε2 sample size to confirm lower thalamic volume in these carriers. Additionally, we will investigate other genetic and environmental risk factors that affect brain structure, modulate healthy brain aging, and predict conversion to MCI or AD.