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<jats:title>Abstract</jats:title> <jats:p>Female sex, age and carriage of the APOE e4 allele are the greatest risk factors for sporadic Alzheimer's disease (AD). The hippocampus has a selective vulnerability to atrophy in ageing that may be accelerated in AD, including in those with increased genetic risk of AD. Within the hippocampal complex, subfields represent cytoarchitectonic and connectivity based divisions. The change in global hippocampal and subfield volume associated with sex, age and APOE e4 status in healthy ageing have not yet been established despite their potential to provide a sensitive biomarker of future vulnerability to AD. Here, we examined non-linear age, sex and APOE effects, and their interactions, on hippocampal and subfield volumes across several decades spanning mid-life to old age in 36 653 healthy ageing individuals. Hippocampal volume showed a marked reduction in APOE e4/e4 female carriers after age 65. Volume was lower in homozygous e4 individuals in specific subfields including the presubiculum, subiculum head, CA1 body, CA3 head and CA4. The findings demonstrate that in healthy ageing, two factors - female sex and APOE e4 status - confer selective vulnerability of specific hippocampal subfields to volume loss.</jats:p>

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