Selective effect of Apo e4 on CA3 and dentate in normal aging and Alzheimer's disease using high resolution MRI at 4 T
Introduction
Apolipoprotein E (Apo e) is a major lipoprotein transporter of the brain and plays an important role in the regulation of the neuronal cholesterol metabolism (Pfrieger, 2003). There are three different isoforms: Apo e2, Apo e3 and Apo e4, which differ by the amino acid residues on sites 112 and 152. Apo e4 has arginine residues at both positions which reduce its stability and render it conformationally unstable. As a consequence, Apo e4 has a lower functionality than the other two isoforms and may even undergo potentially neurotoxic conformational changes (Mahley et al., 2006). Over the last few years, Apo e4 has been implicated as potential genetic risk factor for several neurodegenerative diseases, particularly sporadic Alzheimer's disease (AD) but also multiple sclerosis, Parkinson's disease or amyotrophic lateral sclerosis (Chapman et al., 2001, Bedlack et al., 2000, Blasques et al., 2006). The molecular mechanisms by which Apo e4 promotes neurodegeneration are still not completely understood and most likely complex. In AD for example, it has been shown that Apo e4 not only enhances AD related patho-mechanisms, i.e., increases amyloid production and deposition as well as tau phosphorylation, but also exerts direct neurotoxic effects (Mahley et al., 2006) and impairs neuronal repair/maintenance mechanisms (Weisgraber and Mahley, 1996). Recent studies have also shown that compared to Apo e3, Apo e4 is associated with reduced neuronal plasticity and impaired neurogenesis (Levi et al., 2003, Levi et al., 2005, Levi et al., 2007, Teter, 2004).
The hippocampus is a particularly interesting brain structure in the context of Apo e. It is not only affected by various neurodegenerative conditions (Morrison and Hof, 2002, Mattson et al., 1989, Joels et al., 2004, Velakoulis et al., 2008, Phillips and Reeves, 2001, Gilbert, 2004), but has also a high intrinsic neuroplasticity and is capable of neurogenesis during adulthood (Abrous et al., 2005, Klempin and Kempermann, 2007); all of these are processes which are influenced by the Apo e genotype. The hippocampus is not a homogeneous structure but consists of several subfields with distinct histological characteristics: the subiculum, the three cornu ammonis sectors (CA1-3) and the dentate gyrus. Although these subfields are functionally tightly interconnected (Duvernoy, 2005), there is evidence for a functional specialization (Rolls and Kesner, 2006, Kesner and Hopkins, 2006). Furthermore, animal models and histopathological studies suggest that different disease processes affect subfields selectively, e.g. stress affects predominantly the dentate gyrus while neuron loss in CA1 is typical for AD (West et al., 1994, Lucassen et al., 2006). Therefore, in vivo volumetry of hippocampal subfields might yield a better distinction between different disease processes and/or allow for an earlier diagnosis than measuring global hippocampal volume loss. However, this requires that details of the internal structure of the hippocampal formation can be depicted in vivo. Recent advancements with high field MRI (3–4 T), achieving superb gray/white matter contrast by exploiting increased signal sensitivity, greater dispersion of magnetization transfer effects and enhanced T1 weighting, have resulted in excellent anatomical images at sub-millimeter resolution that can be acquired within a few minutes. In this study, we used high resolution images acquired on a 4 T MRI system and a manual method for subfield marking to address the following aims: 1. To determine if Apo e4 genotype has subfield specific effects in a group of healthy and cognitively intact subjects spanning an age range from 28–85 years. Based on the known actions of Apo e we expected to find an Apo e4 effect in CA1 with the Apo e4 genotype enhancing the age-associated volume loss in this subfield (Mueller et al., 2007), and/or in the dentate gyrus due to a negative impact of Apo e4 on neuroplasticity/neurogenesis (Ji et al., 2003). 2. To study the influence of Apo e4 on hippocampal subfields on AD. Based on histological studies (West et al., 1994), we expected to find a more pronounced volume loss in CA1 in AD with the Apo e4 allele than in AD without it.
Section snippets
Study population
A total of 81 subjects participated in this study. Sixty-six were healthy control subjects (mean age 60.8 ± 13.6, age range: 28–85 years, female/male (f/m) 29/40, mean MMSE 29.4 ± 1.0) recruited from the community with flyers and advertisements in local newspapers. These subjects were recruited with the intention to build a general healthy control population for several ongoing projects in our laboratory and so no special efforts were made to achieve a perfect match between Apo e4 and non-Apo e4
Control population
Apo e4 carrier and non-Apo e4 carrier were not different regarding age or gender distribution. The analysis in the total control population showed a significant effect of Apo e4 (p = 0.042, beta = 9.450) and age (p = 0.021, beta = − 0.786) on CA3&DG with Apo e4 carrier having smaller CA3&DG volumes than non-Apo e4 carrier irrespective of age (cf. Table 1). There was a significant negative effect of age (p = 0.0002, beta = − 1.694) on CA1 volumes confirming the findings of a previous study (Mueller et al.,
Discussion
There were two major findings of this study: 1. Apo e4 was associated with smaller CA3&DG volumes in the whole control population and in the subgroup of old controls but not in the subgroup of young controls. Although total hippocampal volumes tended to be smaller in Apo e4 carriers compared to non-Apo e4 carriers, these differences were not significant. 2. AD with the Apo e4 allele had significantly smaller CA3&DG than AD without the Apo e4 allele. Furthermore, AD patients had smaller ERC,
Disclosure statement
None of the authors has any actual or potential conflicts of interest.
Acknowledgments
The study was supported by grant RO1 AG010897 and P01 AG12435 to Dr. M. W. Weiner and the Department of Veterans Affairs.
References (44)
- et al.
Synaptic loss is accompanied by an increase in synaptic area in the dentate gyrus of ages human apolipoprotein E4 transgenic mice
Neuroscience
(2000) - et al.
Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain
Neuron
(2002) - et al.
Neurons, intracellular and extracellular neurofibrillary tangles in subdivisions of the hippocampal cortex in normal ageing and Alzheimer's disease
Neurosci. Lett.
(1995) Alterations in synaptic transmission and plasticity in area CA1 of adult hippocampus following developmental hypothyroidism
Brain Dev. Brain Res.
(2004)- et al.
Apolipoprotein E isoform specific regulation of dendtritic spine morphology in apolipoprotein E transgenic mice and Alzheimer's disease patients
Neuroscience
(2003) - et al.
Mnemonic functions of the hippocampus: a comparison between animals and humans
Biol. Psychol.
(2006) - et al.
Apo E4 impairs hippocampal plasticity isoform specifically and blocks the environmental stimulation of synaptogenesis and memory
Neurobiol. Dis.
(2003) - et al.
Reduced hippocampal volume in non-demented carriers of the apolipoprotein E ε4: Relation to chronological age and recognition memory
Neurosci. Lett.
(2006) - et al.
Selective vulnerability of corticocortical neurons and hippocampal circuits in aging and Alzheimer's disease
Prog. Brain Res.
(2002) - et al.
Measurements of hippocampal subfields and age related changes with high resolution MRI at 4T
Neurobiol. Aging
(2007)
A computational theory of hippocampal function and empirical tests of the theory
Prog. Neurobiol.
Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease
Lancet
Adult neurogenesis from precursors to network and physiology
Physiol. Rev.
Apolipoprotein E and neuromuscular diseases
Arch. Neurol.
Apolipoprotein E e4 allele in familial and sporadic Parkinson's disease
Neurosci. Lett.
Expression of human apolipoprotein E3 or E4 in the brains of Apoe−/− mice: Isoform specific effects on neurodegeneration
J. Neuroscience.
The effects of APOE genotype on age of onset and progression of neurodegenerative diseases
Neurology
Effect of apolipoprotein E genotype on hippocampal volume loss in aging healthy women
Neurology
Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease
Nat. Genet.
High resolution MRI of the brain at 4.7 Tesla using fast spin echo imaging
Br. J. Radiol.
Hippocampal, amydgalar and global brain atrophy in different apolipoprotein E genotypes
Neurology
The human hippocampus. Functional anatomy, vascularization and serial sections with MRI
Cited by (102)
Apolipoprotein ε4 modifies obesity-related atrophy in the hippocampal formation of cognitively healthy adults
2022, Neurobiology of AgingCitation Excerpt :A recent UK Biobank data analysis found non-linear age-related changes in all subfields of the hippocampal formation (Veldsman et al., 2021). In this study, female APOE ε4 homozygotes over the age of 65 years exhibited the largest atrophy across CA1, CA3, CA4, subiculum and presubiculum, suggesting that age and sex modulated the effects of APOE (Veldsman et al., 2021) (see also Donix et al., 2010; Dounavi et al., 2020; Kerchner et al., 2014; Mueller et al., 2008; Mueller and Weiner, 2009; Reiter et al., 2017). APOE ε4-related volume reductions in the molecular layer of the subiculum and the CA fields were also observed in a middle-aged cohort of cognitively healthy participants, while no effects were present for FH or cardiovascular risk (Dounavi et al., 2020).
Systematic comparison of different techniques to measure hippocampal subfield volumes in ADNI2
2018, NeuroImage: ClinicalMedial temporal lobe subregional morphometry using high resolution MRI in Alzheimer's disease
2017, Neurobiology of AgingHippocampal Subregions Volume and Texture for the Diagnosis of Mild Cognitive Impairment
2024, Experimental Aging Research