APOE ε4 worsens hippocampal CA1 apical neuropil atrophy and episodic memory

Abstract

Objectives: Using high-resolution structural MRI, we endeavored to study the relationships among APOE e4, hippocampal subfield and stratal anatomy, and episodic memory.Methods: Using a cross-sectional design, we studied 11 patients with Alzheimer disease dementia, 14 patients with amnestic mild cognitive impairment, and 14 age-matched healthy controls with no group differences in APOE e4 carrier status. Each subject underwent ultra-high-field 7.0-tesla MRI targeted to the hippocampus and neuropsychological assessment.Results: We found a selective, dose-dependent association of APOE e4 with greater thinning of the CA1 apical neuropil, or stratum radiatum/stratum lacunosum-moleculare (CA1-SRLM), a hippocampal subregion known to exhibit early vulnerability to neurofibrillary pathology in Alzheimer disease. The relationship between the e4 allele and CA1-SRLM thinning persisted after controlling for dementia severity, and the size of other hippocampal subfields and the entorhinal cortex did not differ by APOE e4 carrier status. Carriers also exhibited worse episodic memory function but similar performance in other cognitive domains compared with noncarriers. In a statistical mediation analysis, we found support for the hypothesis that CA1-SRLM thinning may link the APOE e4 allele to its phenotypic effects on memory. Conclusions:The APOE e4 allele segregated dose-dependently and selectively with CA1-SRLM thinning and worse episodic memory performance in a pool of older subjects across a cognitive spectrum. These findings highlight a possible role for this gene in influencing a critical hippocampal subregion and an associated symptomatic manifestation. Neurology ® 2014;82:691-697 GLOSSARY AD 5 Alzheimer disease; aMCI 5 amnestic mild cognitive impairment; ANOVA 5 analysis of variance; CA1-SP 5 CA1 stratum pyramidale; CA1-SRLM 5 CA1 stratum radiatum/lacunosum-moleculare; CDR 5 Clinical Dementia Rating; DG/CA3 5 dentate gyrus and CA3; ERC 5 entorhinal cortex; MTL 5 medial temporal lobe; NIA-AA 5 National Institute on Aging-Alzheimer's Association; OC 5 older control.ApoE influences the metabolism of b-amyloid, the major peptide constituent of amyloid plaques in Alzheimer disease (AD).1 The ApoE4 isoform confers an increased risk of sporadic late-onset AD dementia. 2,3Carriers of the APOE e4 allele who have AD dementia or its clinical precursor, amnestic mild cognitive impairment (aMCI), exhibit greater hippocampal volume loss than noncarriers in some studies, 4-9 although this finding is controversial. [10][11][12] Perhaps these divergent findings arise from disproportionate effects of the e4 allele on individual hippocampal subfields that are not always evident in global volumetric analyses.Specific effects of the APOE e4 allele on hippocampal subfields are of interest. AD-related neuropathology itself is subfield-and even strata-selective, affecting the CA1 subfield, including specifically the stratum radiatum/stratum lacunosum-moleculare (CA1-SRLM), before affecting the remainder of the hippocampus. [13][14][15...

Structural imaging of hippocampal subfields in healthy aging and Alzheimer’s disease

“…Contrastingly, strong correlations were also described in AD patients between delayed recall performance and the widths of CA1-SRLM and CA1-SP, while DG/CA3 size did not significantly correlate with any aspect of memory performance (Kerchner et al, 2012). In a larger and mixed group (controls, MCI and AD patients), Kerchner et al (2014) replicated their first finding of a CA1-SRLM to delayed recall association.…”

“…In a longitudinal study of subfield thickness over two years, the same authors showed a stronger rate of atrophy in the subiculum (Donix et al, 2010b). By contrast, Kerchner et al (2014) found a selective, dose dependent effect on the CA1-SRLM width (yet, controls were pooled with MCI and demented patients in this analysis), while Mueller et al reported a detrimental effect of the ε4 allele on CA3/DG volume in healthy elderly, but not in middle aged individuals (Mueller and Weiner, 2009;Mueller et al, 2008). Overall, the important variability in these results makes it difficult to get a clear picture of the preferential effect of APOE4 on hippocampal subfield volume in asymptomatic individuals.…”

“…Kerchner et al (2010Kerchner et al ( , 2012Kerchner et al ( , 2013Kerchner et al ( , 2014 developed another approach that was directly influenced by several neuropathological studies showing that AD-related neurodegeneration is not only subfield-, but also strata-specific, with a stronger vulnerability of the synapse-rich apical neuropil layer (the stratum radiatum and stratum lacunosum-moleculare, SRLM) as compared to the cell body layer (the stratum pyramidale, SP). Using 7T T2-weighted MR images with ultra high resolution (0.22 x 0.22 x 1.5 mm voxels), they measured different metrics in the body of the hippocampus, including the width (or thickness) of CA1-SRLM, defined as the hypointense band between the more intense DG and CA1-SP cell layers.…”

The Role of MRI Biomarkers and Their Interactions with Cognitive Status and APOE ε4 in Nondemented Elderly Subjects

“…For example, many studies have shown that the APOE ε4 gene affects the hippocampal subfields and cortical thickness in AD and MCI [23, 24]. APOE ε4 allele carriers have shown smaller hippocampal subfields [15, 25, 26] and cortical thickness [24, 27]. The APOE ε4 genotype can modify the correlation between cognitive status and metabolites from the hippocampus [28].…”

P2‐231: Systematic Comparison of Different Techniques to Measure Hippocampal Subfield Volumes in ADNI2

“…These techniques were applied to a variety of diseases in small single-site studies and usually found subfield volumetry to be superior to standard whole hippocampal volumetry for the detection of hippocampal damage in the early stages of the disease process, for differentiating between diseases or for the investigation of structure/function relationships (e.g., Wang et al, 2006;Ballmaier et al, 2008;Mueller et al, 2008;Schobel et al, 2009;Neylan et al, 2010;Bender et al, 2013;Kerchner et al, 2014;SchoeneBake et al, 2014;Chao et al, 2014;Hsu et al, 2015;De Flores et al, 2015;Pluta et al, 2012;Yushkevich et al, 2015b). The promise of hippocampal subfield volumetry techniques however led to two unexpected developments that could potentially limit the usefulness of this approach.…”