APOE ε4 worsens hippocampal CA1 apical neuropil atrophy and episodic memory.
OBJECTIVE
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.
From the Departments of Neurology and Neurological Sciences (G.A.K., D.B., J.C.S., J.D.B., M.C.F., G.K.D., T.W.-C.) and Radiology (B.K.R.), Stanford University School of Medicine, Stanford; and Center for Tissue Regeneration, Repair and Restoration (T.W.-C.), Veterans Affairs Palo Alto Health Care System, Palo Alto, CA.
Geoffrey A
GA
Kerchner
Daniela
D
Berdnik
Jadon C
JC
Shen
Jeffrey D
JD
Bernstein
Michelle C
MC
Fenesy
Gayle K
GK
Deutsch
Tony
T
Wyss-Coray
Brian K
BK
Rutt
D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology; D053327:Apolipoprotein E4 / Q000235:genetics*; D001284:Atrophy; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008568:Memory / Q000502:physiology*; D061212:Memory, Episodic; D008875:Middle Aged; D019581:Neuropil / Q000473:pathology*
D053327:Apolipoprotein E4