Abstract
ObjectiveTo investigate whether there is a specific dose-dependent effect of the Apolipoprotein E (APOE) ε4 and ε2 alleles on hippocampal volume, across the cognitive spectrum, from normal aging to Alzheimer’s Disease (AD).Materials and MethodsWe analyzed MR and genetic data on 662 patients from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database–198 cognitively normal controls (CN), 321 mild-cognitive impairment (MCI) subjects, and 143 AD subjects–looking for dose-dependent effects of the ε4 and ε2 alleles on hippocampal volumes. Volumes were measured using a fully-automated algorithm applied to high resolution T1-weighted MR images. Statistical analysis consisted of a multivariate regression with repeated-measures model.ResultsThere was a dose-dependent effect of the ε4 allele on hippocampal volume in AD (p = 0.04) and MCI (p = 0.02)–in both cases, each allele accounted for loss of >150 mm3 (approximately 4%) of hippocampal volume below the mean volume for AD and MCI subjects with no such alleles (Cohen’s d = −0.16 and −0.19 for AD and MCI, respectively). There was also a dose-dependent, main effect of the ε2 allele (p<0.0001), suggestive of a moderate protective effect on hippocampal volume–an approximately 20% per allele volume increase as compared to CN with no ε2 alleles (Cohen’s d = 0.23).ConclusionThough no effect of ε4 was seen in CN subjects, our findings confirm and extend prior data on the opposing effects of the APOE ε4 and ε2 alleles on hippocampal morphology across the spectrum of cognitive aging.
Highlights
Apolipoprotein E (ApoE), aside from its well-known role as a lipid-transporting entity, plays a key role in many CNS-related processes [1]
There was a dose-dependent effect of the e4 allele on hippocampal volume in Alzheimer’s Disease (AD) (p = 0.04) and mild-cognitive impairment (MCI) (p = 0.02)–in both cases, each allele accounted for loss of .150 mm3 of hippocampal volume below the mean volume for AD and MCI subjects with no such alleles (Cohen’s d = 20.16 and 20.19 for AD and MCI, respectively)
Though no effect of e4 was seen in CN subjects, our findings confirm and extend prior data on the opposing effects of the Apolipoprotein E (APOE) e4 and e2 alleles on hippocampal morphology across the spectrum of cognitive aging
Summary
Apolipoprotein E (ApoE), aside from its well-known role as a lipid-transporting entity, plays a key role in many CNS-related processes [1]. The e2 variant has been repeatedly shown to have nearly perfectly-opposing effects: it is markedly underrepresented in AD cases, and is associated with a delayed age-of-onset of AD as well as with decreased amounts of AD-related brain pathology in affected patients [3,4,5]. It has been argued that ApoE in general serves primarily neurotrophic and neuro-protective roles, and that associations of e4 with higher risk for and more disease is due more to absence of the e2/3 isoforms than it is the presence of e4– a more than semantic distinction [9]
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