Structural brain volume differences between cognitively intact ApoE4 carriers and non-carriers across the lifespan

Ryan J. Piers

Department of Psychological and Brain Sciences, Boston University, Boston, MA, USA

Abstract Apolipoprotein E4 (ApoE4) is a prominent genetic risk factor for Alzheimer’s disease. The purpose of this review is to explore differences in structural brain volume detected by magnetic resonance imag‐ing between cognitively intact ApoE4 carriers and non‐carriers across the lifespan (i.e., older adults,middle‐aged adults, young adults, children and adolescents, and neonates). Consistent findings are found throughout various developmental stages. This area of research may elucidate the mechanisms by which ApoE4 in fluences risk of developing Alzheimer’s disease. It could also inform potential treat‐ment strategies and interventions for carriers of the ApoE4 allele.

Key Words: MRI; healthy aging; genetic risk factor; biomarker; Alzheimer’s disease

Introduction

Apolipoprotein E4 (ApoE4) is a prominent genetic risk factor for Alzheimer’s disease (AD). An individ‐ual can be a carrier of one or two ApoE4 alleles, or a non‐carrier. The risk of developing AD increases expo‐nentially as the number of alleles increases. One study reported that the lifetime risk of AD is between 51%and 60% for men and women who are carriers of two ApoE4 alleles and between 23% and 30% for men and women who are carriers of one ApoE4 allele (Genin et al., 2011). Apolipoprotein E2 (ApoE2) and apolipopro‐tein E3 (ApoE3) alleles also exist, and ApoE2 has been shown to have a neuroprotective effect (Wu and Zhao,2016).

The purpose of this review is to explore structural brain volume differences between cognitively intact ApoE4 carriers and non‐carriers. What this review contributes to the literature is an examination of struc‐tural differences across the lifespan. As such, the re‐view is broken into various developmental stages. Giv‐en the strong association between ApoE4 and AD, it is expected that structural differences exist in areas com‐monly targeted by AD, most notably medial temporal structures such as the hippocampus and entorhinal cortex. This area of research may elucidate the mech‐anisms by which ApoE4 in fluences risk of developing AD. It could also inform potential treatment strategies and interventions for carriers of the ApoE4 allele.

ApoE4 and Magnetic Resonance Imaging(MRI) Findings in Healthy Individuals

Older adults

Honea et al. (2009) investigated the impact of ApoE status on structural brain volume in cognitively healthy older adults over the age of 60 years (mean age = 73.4 years, SD = 6.3). Participants were grouped by genotype: ApoE4 carriers (4/4, 4/3) and ApoE4 non‐carriers. MRI was used to assess structural brain volume differences between the groups. The areas of interest included the hippocampus, amygdala, precu‐neus, inferior parietal cortex, superior frontal cortex,and angular/supramarginal gyrus. The results showed significantly less hippocampal and amygdala volume in ApoE4 carriers relative to non‐carriers. This finding is signi ficant because the hippocampus and amygdala(both part of the medial temporal cortex) are brain regions known to undergo accelerated atrophy in mild cognitive impairment (MCI) and AD (Basso et al.,2006; Schuff et al., 2009).

Middle-aged adults

Burggren et al. (2008) examined ApoE status and its association with structural brain volume and cortical thickness in cognitively healthy middle‐aged adults.Participants were grouped by genotype: ApoE4 carri‐ers (all 4/3) and ApoE4 non‐carriers (all 3/3). Using MRI, they measured several subregions of the medial temporal lobe, specifically the hippocampus, dentate gyrus, entorhinal cortex, subiculum, perirhinal cor‐tex, parahippocampal cortex, and fusiform gyrus. It was found that ApoE4 carriers had significantly less cortical thickness in the entorhinal cortex and the subiculum as compared to non‐carriers. The entorhi‐nal cortex (which was not examined in Honea et al.,2009) is associated with neuropathology and volume loss in early AD (Braak and Braak, 1991; Bobinski et al., 1999). Contrary to the results of Honea et al. (2009),Burggren et al. did not find significant differences in hippocampal volume. This study strengthens the find‐ings of Honea et al. because ApoE4 status was found to in fluence differences in cortical thickness in subregions of the medial temporal lobe (an area associated with signi ficant morphological change in MCI and AD) in cognitively healthy, middle‐aged adults.

Young adults

O’Dwyer et al. (2012) studied whether young adult ApoE4 carriers and non‐carriers differ in terms of brain volume. Participants between 20 and 38 years of age (mean = 26.8, SD = 4.6) were grouped by gen‐otype: ApoE4 carriers (4/4, 4/3) and ApoE4 non‐car‐riers (3/3). The areas of interest included the nucleus accumbens, amygdala, caudate nucleus, hippocampus,pallidum, putamen, thalamus, and brain stem. O’Dw‐yer et al. reported signi ficantly less right hippocampal volume in ApoE4 carriers compared to non‐carriers.Furthermore, they found a borderline significant re‐duction in left hippocampal volume in ApoE4 carriers compared to non‐carriers. Surprisingly, no signi ficant differences were observed in other brain areas, includ‐ing the amygdala. This study is consistent with Honea et al. (2009), and contrasts with Burggren et al. (2008)in terms of the differences in hippocampal volume observed between ApoE groups. However, this study con flicts with Honea et al. in that they did not find dif‐ferences in amygdala volume between groups.

Similar to Honea et al., O’Dwyer et al. combined 4/4 and 4/3 participants to create an ApoE4 carrier group.The inclusion of the ApoE4 carrier group could possi‐bly explain the signi ficant result for hippocampal vol‐ume in both studies. Interestingly, O’Dwyer et al. only found significantly less right hippocampal volume,suggesting that the right hippocampus is more suscep‐tible to atrophy than the left hippocampus in ApoE4 carriers. Future studies should examine whether cog‐nitive deficits are present in these individuals, and if so, elucidate whether less right hippocampal volume is associated with the same degree of cognitive decline as in ApoE4 carriers with less total hippocampal volume(Honea et al., 2009). O’Dwyer et al. provides further evidence of the in fluence of ApoE4 on the volume of medial temporal lobe subregions in cognitively healthy individuals.

Children and adolescents

Shaw et al. (2007) investigated the impact of ApoE status on cortical morphology in children and adoles‐cents. Participants were grouped by genotype: ApoE4 carriers (4/4, 4/3) and ApoE4 non‐carriers (2/3, 3/3).The researchers examined structural differences be‐tween groups with respect to a number of areas, in‐cluding the entorhinal cortex, medial temporal cortex,and orbitofrontal cortex. Shaw et al. found that com‐pared to non‐carriers, ApoE4 carriers showed signi fi‐cantly thinner cortical thickness of the left entorhinal cortex. Although nonsignificant, ApoE4 carriers had thinner cortical thickness of the right entorhinal cor‐tex as well. Furthermore, in the left entorhinal cortex,medial temporal cortex, and orbitofrontal cortex, the researchers observed that ApoE2 (2/3) carriers had the greatest cortical thickness, followed by ApoE3 homo‐zygotes, while ApoE4 carriers had the thinnest cortical volume. The increased cortical thickness observed in ApoE2 carriers is a possible explanation for ApoE2’s suggested neuroprotective properties. Significant group differences were not found in other brain areas,including the frontal, parietal, occipital, and lateral temporal cortex. In sum, Shaw et al. demonstrated that signi ficant ApoE allele‐speci fic structural brain differ‐ences can be observed as early as childhood. Consistent with Burggren et al. (2008) findings, Shaw et al. found differences in the entorhinal cortex, a brain region as‐sociated with neuropathology and volume loss in early AD (Braak and Braak, 1991; Bobinski et al., 1999).Furthermore, consistent with all studies presented thus far, they found evidence of the in fluence of ApoE4 on the volume of medial temporal lobe subregions in cog‐nitively healthy individuals.

Neonates

Knickmeyer et al. (2014) examined the impact of ApoE status on structural brain volume in neonates.Neonates were grouped by genotype: ApoE4 carriers(4/3) and ApoE4 non‐carriers (3/3). Brain areas exam‐ined include temporal, frontal, and parietal lobes, and their subregions. Knickmeyer et al. (2014) found that ApoE4 carriers had less volume in multiple brain ar‐eas, including the temporal, frontal, and parietal lobes.The researchers also observed less volume in temporal subregions for ApoE4 carriers, including the bilateral hippocampus, parahippocampus, fusiform, and middle and inferior temporal gyri. The differences found in hippocampal volume are consistent with Honea et al.(2009) and O’Dwyer et al. (2012). This study demon‐strated that ApoE status‐dependent morphological brain differences can be observed in individuals shortly after birth.

Table 1 Structural brain volume differences between cognitively intact ApoE4 carriers and non-carriers across the lifespan

Longitudinal examination

A limitation of all the preceding studies is their cross‐sectional design. Longitudinal studies may fur‐ther elucidate the influence of ApoE4 on structural morphological changes in healthy individuals because such studies allow researchers examine how these changes progress over time.

In one longitudinal study, Lu et al. (2011) investi‐gated differences in atrophy rates for ApoE4 carriers(all 4/3) and non‐carriers (2/3). Healthy older adults between the ages of 55 and 75 were grouped by geno‐type: ApoE4 carriers (all 4/3) and ApoE4 non‐carriers(all 2/3). They examined frontal, temporal, parietal, oc‐cipital lobes, and the hippocampus. Participants com‐pleted baseline and 5‐year follow‐up MRI assessments.Lu et al. found more extensive annual atrophy rates of temporal lobe and hippocampal region in ApoE4 carriers compared to non‐carriers. Furthermore, more extensive annual atrophy rates were found speci fically in the right hippocampus. No signi ficant differences in annual atrophy rates were observed in the left hippo‐campus. This result is consistent with O’Dwyer et al.(2012). In sum, this study highlighted the importance of studying longitudinal change in right hippocampus volume in ApoE4 carriers as a potential preclinical biomarker of AD.

Discussion

ApoE4 and structural MRI findings in healthy indi‐viduals have been studied in older adults, middle‐aged adults, young adults, children and adolescents, and ne‐onates. Convincing evidence exists which suggests re‐gionally speci fic effects of the ApoE4 allele on structur‐al brain morphology, speci fically the medial temporal cortex and its subregions (the hippocampus, amygdala,entorhinal cortex, and subiculum; see Table 1).

There are a number of limitations of the current lit‐erature. Several of the articles (Burggren et al. 2008;Honea et al., 2009; O’Dwyer et al., 2012) provided incomplete demographic information (e.g., race/eth‐nicity) for the sample, making it difficult to determine the generalizability of the results. Furthermore, Knick‐meyer et al. (2014) involved an all‐white sample. As a result, it cannot be concluded that the influence of ApoE4 on brain morphology is generalizable to other racial and ethnic groups. Future research should re‐cruit participants from a diverse range of multicultural backgrounds.

When conducting research on cognitively intact in‐dividuals, researchers must ensure that the participants are, in fact, cognitively healthy. Using a Clinical De‐mentia Rating (CDR) score alone to determine wheth‐er older adults are cognitively intact (Honea et al.,2009) may not be sufficient. The use of multiple mea‐sures (Burggren et al., 2008; Lu et al., 2011) makes for a far more valid assessment of cognitive health. Also,consistent with the literature, there are limitations to the validity of self‐report measures because of their in‐herent subjectivity (Robinson and Clore, 2002).

Several studies grouped subjects into ApoE4 carriers and non‐carriers (Shaw et al., 2007; Honea et al., 2009;O’Dwyer et al., 2012). That is, some combination of 4/4, 4/3, and 4/2 made up carriers, while some com‐bination of 3/3, 2/3, 2/2 made up non‐carriers. These grouping strategies make it difficult to determine the unique contribution of homozygote ApoE4 (genetic risk factor for of AD) and homozygote ApoE2 (neuro‐protective). Future research should investigate 4/4, 4/3,4/2, 3/3/, 2/3, and 2/2 groups independently, as seen in Burggren et al. (2008), Lu et al. (2011), and Knickmey‐er et al. (2014).

In closing, most of the existing literature on ApoE4 and structural MRI findings in healthy individuals in‐volves cross‐sectional examination (Shaw et al., 2007;Burggren et al., 2008; Honea et al., 2009; O’Dwyer et al., 2012; Knickmeyer et al., 2014). Therefore, it is not possible to con firm whether these morphological brain changes are, in fact, preclinical markers of AD. Longi‐tudinal studies that track participants throughout the lifespan are needed; especially ones that monitor how these morphological brain changes relate to cogni‐tive performance (Wolf, 2012). If conclusive evidence emerges that these ApoE status‐dependent structural brain differences — which can be detected shortly after birth (Knickmeyer et al., 2014) — do represent risk fac‐tors for later cognitive decline and AD, they provide particularly promising targets for treatment strategies and interventions.

Author contributions:RJP conceived and designed the paper, reviewed the literature and wrote the paper, and approved the final version of the paper.

Conflicts of interest:None declared.

Financial support:None.

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