Our data indicate that among cognitively healthy APOE-4 carriers the rate of cortical thinning over time is significantly greater in SUB and ERC when compared to non-carriers of the APOE-4 allele. Global cortical thinning (average across subregions) was also significantly greater among APOE-4 carriers. Within group, non-APOE-4 carriers did not show cortical thinning over time whereas APOE-4 carriers showed decrease in cortical thickness in all subregions except CA23DG.
The APOE-4 allele is recognized as the most important genetic risk factor for sporadic AD known today (Brouwers et al., 2008
). Using different neuroimaging techniques several studies have revealed structural and functional brain characteristics among cognitively healthy APOE-4 allele carriers that may be associated with AD risk (e.g., Bookheimer et al., 2000
; Burggren et al., 2008
; Reiman et al., 2005
). However, APOE-4 associated characteristics are already present in children and young adults (Reiman et al., 2004
; Shaw et al., 2007
). For example, Shaw et al. (2007)
found a thinner ERC in children carrying the APOE-4 allele. This could represent a genetically determined neuroanatomic property, effectively a static risk factor, such that less thinning may be required to develop clinical symptoms once a neurodegenerative process starts later in life (Shaw et al., 2007
). It is unlikely that in this case the thinner ERC itself reflects pathology. Cortical thinning in children and adolescents is associated with physiological cortical maturation (Sowell et al., 2001
). The thinner ERC may represent a more mature cortex, which could be beneficial with respect to cognitive performance. There is evidence for early developmental benefits associated with the APOE-4 genotype, resulting in greater verbal fluency abilities (Alexander et al., 2007
), or a more economic use of learning-related neural resources (Mondadori et al., 2007
). The relatively high prevalence of the APOE-4 allele in the general population is also in line with the allele’s possible antagonistically pleiotropic effects (Wright et al., 2003
). However, Sowell et al. (2001)
demonstrated that in children frontal lobe gray matter thinning/maturation was more predictive for cognitive performance than cortical structure changes within the MTL.
Few studies have demonstrated longitudinal changes in brain structure and function in cognitively intact APOE-4 carriers. It has been shown that there is greater decline in brain glucose metabolism when comparing middle-aged healthy APOE-4 carriers and non-carriers in a 2-year follow-up (Small et al., 2000
). Chen et al. (2007)
reported greater whole brain atrophy in 47- to 68-year-old cognitively normal homozygous but not heterozygous APOE-4 subjects compared to subjects not carrying the APOE-4 allele within a 2-year period, suggesting that APOE-4 gene dose contributes to longitudinal morphological changes. The authors used two different image analysis methods (brain boundary shift integration/iterative principal component analysis; Chen et al., 2007
) and reported annual atrophy rates of 0.08%/0.43% for non-APOE-4 carriers, 0.18%/0.58% for heterozygous APOE-4 carriers, and 0.37%/0.76% for homozygous APOE-4 carriers. Cohen et al. (2001)
found significantly greater percent of change in hippocampal volume due to APOE-4 genetic risk (annual rate: 2.3% for APOE-4 carriers, and 0.77% for non-carriers). Our volumetric data show a similar magnitude of volume loss over time, although we did not find significant volumetric effects. However, studies examining the association between APOE genotype and hippocampal volume have shown mixed results (Cherbuin et al., 2008
; Jack et al., 1998
). Burggren et al. (2008)
demonstrated that measuring cortical thickness might better reflect morphological changes of the layered cortical architecture than hippocampal volume. They showed that cortical thickness but not volume was reduced in SUB and ERC among cognitively healthy APOE-4 participants when compared to non-APOE-4 carriers. The present study similarly indicates greater sensitivity of subregional thickness measures compared to overall volume in longitudinal changes in an at-risk population. Our data suggest a dynamic process of thickness decline in elderly subjects. Aging is associated with decreased synaptic plasticity and reduced hippocampal neurogenesis (Cameron and McKay, 1999
). APOE proteins are involved in neuronal plasticity and repair processes, possibly through isoform-specific functions in cholesterol and phospholipid metabolism. The presence of the APOE-3 allele stimulates neuronal growth in cell cultures, whereas the APOE-4 allele is associated with decreased or inhibited neuronal sprouting (Teter et al., 2002
). It is therefore likely that age-related decline in MTL thickness would be more pronounced in APOE-4 carriers due to lower neuronal repair efficiency. This would suggest vulnerability for AD but does not necessarily reflect AD pathology. Alternatively, greater cortical thickness decline in ERC and SUB of older APOE-4 carriers may be due to cellular processes related to AD pathology. ERC is the first region showing AD-related neurofibrillary tangle deposition, perhaps decades before the onset of clinical symptoms (Ohm et al., 1995
), that later spreads to SUB and CA fields (Braak and Braak, 1991
Although between-group patterns in baseline cortical thickness differ from our previous study (Burggren et al., 2008
), we suggest that our recruitment strategy, which was to select subjects that were cognitively healthy at two time points, could contribute to this finding. Subjects that were cognitively healthy at baseline but later developed MCI were excluded from the analysis as we wanted to focus on subjects in the “normal” range of cognition. The rigorous selection of longitudinally stable healthy subjects may have biased our sample towards finding study participants that were equivalent in cortical thickness metrics at baseline; a more random selection of subjects might have shown greater differences in hippocampal structure at baseline. Additionally, more non-APOE-4 carriers and fewer APOE-4 subjects in this study compared to our previous study (Burggren et al., 2008
) had a family history of AD; there was no overlap in the subject population between these studies. Family history risk of AD may reflect yet unknown genetic and non-genetic risks for AD. We recently demonstrated that family history of AD is associated with reduced cortical thickness of medial temporal lobe subregions independent of APOE genotype (Donix et al., 2010
). Our data suggest that if we had assessed subjects at a slightly later date we would have found baseline cortical thickness differences. It is unclear, however, whether this would have affected the annual rate of longitudinal cortical thinning. The possible relationship between baseline thickness and rate of longitudinal change should be investigated in future studies.
This study has several limitations: Our subject sample size is relatively small, limiting our ability to draw broader conclusions across a range of subject characteristics including age of assessment and family history, to name a few. AD risk factors possibly contributing to having a family history for AD, such as cerebral vascular risk and shared environmental factors could differ between subjects. It is also not possible to determine whether these patterns would be representative for the general population, as our APOE-4 subjects may represent a uniquely healthy risk group and our APOE-3 subjects have a relatively high rate of family history risk. Future examination of cognitively impaired people differing in APOE genotype status using the same image analysis technique could help determine whether the effects seen in this study are driven by subclinical disease. The causes of cortical thinning cannot be revealed using MRI alone. Further longitudinal investigations should examine whether specific patterns of cortical thickness change are associated with the subsequent decline into AD and which anatomical features might be related to pathological versus normal aging.
In summary, we found that subjects carrying the APOE-4 allele when compared to non-carriers show greater decline in cortical thickness in SUB and ERC over a 2-year interval. Our results contribute to the hypothesis that the APOE-4 allele determines a neuroanatomic endophenotype that renders individuals at a higher risk for developing AD due to its different cortical architecture. These structural characteristics could be more dynamic as we age, when APOE-4 related impairment in synaptogenesis and neuronal repair is likely to have greater impact. Other variables, such as a family history of AD could be additionally modulating factors that may contribute to reach a critical threshold in neuronal integrity. Whether this is a necessary condition for the development of AD or may itself represent a first stage of a neurodegenerative disorder remains unknown.