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 ε4, 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 ε4 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 ε4 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 ε4 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 ε4 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 ε4 allele to its phenotypic effects on memory.

Conclusions: The APOE ε4 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.

Figure. Dose-dependent effects of the APOE ε4 allele on MTL structure and memory performance

(A) Relative subfield sizes are expressed as z-transformed residuals after adjustment for diagnostic group membership (control, aMCI, or AD dementia), illustrated according to the number of APOE ε4 alleles (0, 1, or 2). Anatomical metrics include the cross-sectional area of the overall hippocampus; widths of the ERC, CA1-SRLM, and CA1-SP; and cross-sectional area of the DG/CA3. Error bars represent standard error. *p < 0.05 for the main effect of ε4 dose on subfield size (1-way ANOVA). (B) Relative memory subtest scores are expressed as z-transformed residuals after adjustment for diagnostic group membership (control, aMCI, or AD dementia), illustrated according to the number of APOE ε4 alleles. See the subjects section under methods for an explanation of the immediate, delayed, and recognition composite metrics. Error bars represent standard error. *p < 0.05 for the main effect of ε4 dose on composite subtest metric (1-way ANOVA). AD = Alzheimer disease; aMCI = amnestic mild cognitive impairment; ANOVA = analysis of variance; DG/CA3 = dentate gyrus and CA3; ERC = entorhinal cortex; Hipp = hippocampus; MTL = medial temporal lobe; SP = stratum pyramidale; SRLM = stratum radiatum/lacunosum-moleculare.