APOE ε4 worsens hippocampal CA1 apical neuropil atrophy and episodic memory

Objectives:Using high-resolution structural MRI, we endeavored to study the relationships among APOE epsilon 4, 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 epsilon 4 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 epsilon 4 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 epsilon 4 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 epsilon 4 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 epsilon 4 allele to its phenotypic effects on memory.Conclusions:The APOE epsilon 4 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.