No ɛ4 gene dose effect on hippocampal atrophy in a large MRI database of healthy elderly subjects
Introduction
The apolipoprotein E (ApoE) gene is localized on the chromosome 19 in a single locus with three alleles (ɛ2, ɛ3, and ɛ4) responsible for the three major ApoE isoforms (ApoE-2, ApoE-3, and ApoE-4)(Zannis et al., 1982). ApoE is a plasma glycoprotein involved in the transport of cholesterol and other lipids across the membrane of various cells (Mahley, 1988). It is also produced in the brain and appears to be involved in cell growth and regeneration of nerves during development as well as following injury. The ɛ4 allele of the ApoE gene is a well-established risk factor for Alzheimer's disease (Corder et al., 1993), and numerous studies have reported higher frequency of the ɛ4 allele among patients with late onset (after 65 years) Alzheimer's disease (Rocchi et al., 2003, Strittmatter et al., 1993), the risk increasing with the number of ɛ4 alleles (Farrer et al., 1997). Although the precise role of ApoE on the pathophysiology of Alzheimer's disease remains uncertain, ApoE is present in the senile plaques and the neurofibrillary tangles (Namba et al., 1991), the two major lesions characterizing Alzheimer's disease (Braak et al., 1999). Moreover, Alzheimer's patients carrying the ɛ4 allele have an increased number of plaques and tangles as compared to noncarriers (Nagy et al., 1995), and a positive correlation between the amount of neurofibrillary tangles and/or senile plaques in the brain and the number of ɛ4 alleles has been reported (Marz et al., 1996).
Several magnetic resonance imaging (MRI) studies have attempted to map brain structural changes associated with the polymorphism of the ApoE gene in Alzheimer's patients. From these studies, an ɛ4 gene dose effect on the hippocampal atrophy has been reported in Alzheimer's patients (Geroldi et al., 1999). Meanwhile, Lehtovirta et al. (1995) have demonstrated that, as compared to healthy controls, ɛ4 homozygous patients had a more pronounced right hippocampal atrophy than ɛ4 heterozygotes or noncarrier patients while these last two groups exhibited similar right hippocampal volumes.
In nondemented elderly subjects, however, such a gene dose effect on hippocampal atrophy has not been firmly established. Due to the very low frequency of ɛ4 homozygous subjects, most studies have not been aimed at investigating the existence of an ɛ4 gene dose effect. Rather, they focused on a comparison between ɛ4-carriers and noncarriers, pooling homozygotes and heterozygotes in a single group. For instance, while Tohgi et al. (1997) found a reduction of the right hippocampus volume in ɛ4-carriers, Geroldi et al. (1999) did not find this relation for the left or right hippocampal volumes. Note that although Moffat et al. (2000) did not find any significant hippocampal volume difference between ɛ4-carriers and noncarriers, they reported a larger annual rate of hippocampal volume loss in ɛ4-carriers as compared to noncarriers. In other hand, some studies have attempted to compare either homozygotes or heterozygotes, but not both, to noncarriers. Plassman et al. (1997) reported a bilateral reduction of hippocampal volume in ɛ4 heterozygotes as compared to noncarriers. Surprisingly, Reiman et al. did not find reduction of left or right hippocampal volume in ɛ4 homozygotes compared with noncarriers (Reiman et al., 1998). Longitudinally, Cohen et al. showed a greater annual rate of hippocampal volume loss in ɛ4 heterozygotes than in noncarriers while there was no difference between these two groups for hippocampal volume at the time of entry into the study (Cohen et al., 2001).
Currently, only two studies have searched for an ɛ4 gene dose effect on hippocampal atrophy, reporting partly conflicting results. Soininen et al. (1995) did not find differences between the right or left hippocampal volume of ɛ4 homozygotes, ɛ4 heterozygotes, and noncarriers. On the other hand, Den Heijer et al. (2002) reported a decrease of hippocampal volume in ɛ4-carriers as compared to noncarriers, the decrease being larger in homozygotes than in heterozygotes.
To sum up, significant discrepancies exist in the literature dealing with the relationships between the ApoE genotype and hippocampal atrophy. Several experimental design factors are likely to contribute to such discrepancies, including sampling characteristics (most studies had small samples, except for the Den Heijer et al., 2002, study) and the variety of hippocampal volume measurement methods. In the present study, we have attempted to alleviate these limits, investigating an ɛ4 gene dose effect on grey matter atrophy in a sample of 750 healthy elderly subjects, using a fully automated image analysis. In addition, while we focused on hippocampal volume, as previous authors did, we also extended our investigation over the whole grey matter using a voxel-based approach.
Section snippets
Subjects
The sample of subjects who participated in the present protocol is a subsample of the Epidemiology of Vascular Aging (EVA) cohort (n = 1389), a longitudinal study on vascular aging and cognitive decline, the characteristics of which have been described elsewhere (Dufouil et al., 2001). Subjects, born between 1922 and 1932, were recruited over a 2-year period (June 1991 to June 1993) from electoral rolls in Nantes (France). At 4-year follow-up, an MRI examination was proposed to all subjects,
Results
At the time of the MRI examination, the ɛ4 (−/−), ɛ4 (+/−), and ɛ4 (+/+) groups did not significantly differ for age, sex ratio, hypertension, education level, and MMSE score (see Table 1). During the 7-year follow-up, cognitive impairment occurred in 125 subjects among the initial 750. After adjusting for age, sex, education level, time after inclusion, and initial cognitive performances, the risk of cognitive impairment was found multiplied by a factor 5.9 (95% CI = [1.5, 30]; P = 0.03) in
Discussion
The major findings of the present study are as follows: firstly, the absence of a reduced hippocampal volume in heterozygotes as compared to noncarriers, in apparent contradiction with previous studies that reported evidence of an ɛ4 gene dose effect on hippocampal atrophy; and secondly, the confirmation of a specific hippocampal atrophy in homozygotes.
Acknowledgments
The authors are greatly indebted to Dr. Nathalie Tzourio-Mazoyer for the MNI single-subject brain parcellation. This work has been conducted within the framework of the ICBM project (http://www.loni.ucla.edu/ICBM/).
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