Regular articleAssociations between Alzheimer’s disease polygenic risk scores and hippocampal subfield volumes in 17,161 UK Biobank participants
Introduction
Hippocampal atrophy is one of the most validated and widely used biomarkers of Alzheimer’s disease (AD) (de Flores et al., 2015). However, the hippocampus is not a homogenous structure and differential vulnerability of the hippocampal subfields to neurodegeneration has been reported to affect different cognitive functions (Mueller et al., 2010). Decline in volumes of hippocampal subfields have been associated with age and sex. Studies in healthy adults have shown significant age effects in cornu ammonis (CA)1-2 (Daugherty et al., 2016; Mueller et al., 2007; Pini et al., 2016; Shing et al., 2011; Wisse et al., 2014), dentate gyrus (DG) (Daugherty et al., 2016; Wisse et al., 2014), and CA4 volumes (Wisse et al., 2014). Evidence has been presented for an anterior-posterior gradient in hippocampal volume reduction (Malykhin et al., 2017) with age, which implies that the hippocampal subregions are not uniformly affected along the hippocampal axis. Significant decreases in CA1 and subiculum volumes and shape have been observed in participants with mild cognitive impairment (MCI) and AD (de Flores et al., 2015; Pini et al., 2016). Moreover, sex differences in hippocampal subfield volumes have also been observed—males had larger parasubiculum, fimbria, hippocampal fissure, and presubiculum—whereas females had larger volumes for the hippocampal tail (van Eijk et al., 2020). It has also been shown that total hippocampal volume loss in females was more pronounced than males (Nobis et al., 2019). However, to date, there is a lack of studies examining sex differences of hippocampal subfield volumes in greater detail. Therefore, it is important to further study the impact of normal aging and sex on hippocampal subregions and to determine whether AD genetic risk selectively and differentially impacts distinct subfields.
Although one heritability study using twins by Elman et al. (2019) showed little genetic impact on subfields after accounting for total hippocampus volume, a recent genome-wide association study (GWAS) on hippocampal subfield volumes derived from FreeSurfer reported that genetic determinants varied across different subregions (van der Meer et al., 2018). The authors found that the volumes of all hippocampal subfields were heritable in individuals with a mean age of approximately 47.8 (standard deviation = 17.3) years (h2 range: 0.14–0.27). They identified genome-wide significant single nucleotide polymorphisms (SNPs) associated with the whole hippocampus, presubiculum, subiculum, CA1, DG, molecular layer, and hippocampal tail. In addition, in their follow-up analyses on age-stratified subsamples, they also investigated the genetic overlap with AD and showed that 3 of the significant SNPs were associated with hippocampal subfield volumes in the older age group. This study showed that the differences in cytoarchitecture of the hippocampal subfields are partially driven by genetic variation and that AD-related genes may influence the hippocampal volume predominantly later in life.
Previous studies have identified several common risk variants for AD beyond the well-established apolipoprotein E epsilon 4 allele (APOE-ε4) (Li et al., 2018; Xiao et al., 2017). However, these risk alleles have shown small effects on disease risk (Desikan et al., 2015; Lambert et al., 2013). Other studies have used the AD polygenic risk score (PRSAD) to examine the cumulative genetic risk for AD (Dezhina et al., 2018; Li et al., 2018), which has shown improvements in predicting cognitive decline beyond the APOE locus (Escott-Price et al., 2015).
As hippocampal subfield volumes are differentially affected in the early stages of AD (Zhao et al., 2019), it is possible that this is driven by the genetic risk for AD. Moreover, the PRSAD may have a differential effect on the subfield volumes in a cohort of non-demented individuals. To date, there has not been any study to investigate the relationship between PRSAD and hippocampal subregions, which could help understand the relationship among AD genetic risk factors, aging, and the pathobiology of AD.
The overall aim of this study is to investigate hippocampal volume subfields in greater detail in a large cohort using the UK Biobank data of n = 17,161 participants. The study had 3 main objectives: (1) to investigate the relationships among age, sex, and hippocampal subfield volumes; (2) to examine the effects of PRSAD constructed using genome-wide significant AD risk variants (Lambert et al., 2013) on hippocampal subfield volumes; and (3) to study the interaction of age and sex with the effects of PRSAD. We hypothesized that age and sex would be associated with hippocampal subfield volumes. We also hypothesized that there would be varying effects of PRSAD across the different hippocampal subfield volumes, with higher genetic risk of AD being differentially associated with lower hippocampal subfield volumes. We also hypothesized that PRSAD would be modulated by age and sex on hippocampal subfield volumes.
Section snippets
Participants
The UK Biobank, which is a large prospective cohort study, included participants from the United Kingdom aged between 40 and 80 years old (Sudlow et al., 2015). Participants provided full informed consent to participate in the UK Biobank and ethics approval was given by the National Health Service National Research Ethics Service (Ref 11/NW/0382).
For this study, cross-sectional data released in January 2019 were used. UK Biobank provided 19,363 participants who had T1-weighted magnetic
Age-sex differences in hippocampal subfield volumes
As shown in Table 1, of the 17,161 total participants, 9256 (53.9%) were female and the mean (standard deviation) age was 62.39 (7.43) years. Table 1 shows the hippocampal subfield volumes, showing no significant differences between right and left hemispheres.
All hippocampal subfield volumes were negatively associated with age (Supplementary Table 1, Supplementary Fig. 1). Sex was associated with all hippocampal subfield volumes, except for the left hippocampal tail, with women having lower
Discussion
The main findings of this study are the following: (1) hippocampal subfield volumes are associated with age and sex; (2) higher PRSAD is associated with lower hippocampal subfield volumes in the left and right whole hippocampus, bilateral HATA, bilateral hippocampal tail, right subiculum, left CA1, left CA4, left molecular layer, and left CG-DG, which suggests differential effect of PRSAD on the hippocampal subfield volumes; (3) modulation of PRSAD by age, but not sex, on hippocampal subfield
Conclusion
This study shows that the genetics of AD, specifically the APOE locus, is a contributing factor for the differential hippocampal subfield vulnerabilities seen in non-demented older adults, and the pattern of volume loss seems to be similar to that observed in the early stages of AD. The effect of PRSAD and specific hippocampal subfield volumes may be useful in allowing us to understand the genetic effects on individual subfields. It furthers our knowledge of the association of AD risk with
Acknowledgements
Many thanks to the UNSW Scientia PhD Scholarship Program for their support to Heidi Foo. This research has been conducted using the UK Biobank Resource (Project ID: 37103).
Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this
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