The selective vulnerability of the left fimbria in cognitively normal APOE ε4 carriers: a localized structural correlate of high genetic risk for Alzheimer's disease.

The apolipoprotein E ε4 (APOE ε4) allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), yet the earliest structural brain alterations associated with ε4 risk remain insufficiently characterized. Here, we utilized a discovery-validation framework to investigate whether cognitively normal APOE ε4 carriers exhibit selective hippocampal subfield alterations and evaluated their relationship with cognitive performance. High-resolution structural MRI from the PEARL-Neuro and ADNI cohorts was processed using FreeSurfer to quantify volumes of 19 hippocampal subfields. Cognitive performance was assessed using the Everyday Cognition scale (Ecog) for ADNI and the California Verbal Learning Test (CVLT) for PEARL-Neuro. Group comparisons and partial correlations examined the structural and cognitive correlates of APOE ε4 status. A selective reduction in left fimbria volume was initially discovered in the PEARL-Neuro cohort (uncorrected p < 0.001, surviving the Bonferroni-corrected threshold of p < 0.0026), and a targeted analysis in the larger ADNI cohort showed a statistically significant but smaller reduction (p = 0.015). Combined analysis confirmed an overall left fimbria difference while total hippocampal volume remained preserved. Notably, a significant Genotype × Cohort interaction indicated a cohort-dependent effect magnitude, limiting the assumption of a uniform cross-cohort effect. In ADNI, smaller left fimbria volume correlated with poorer language-related Ecog SP performance (p = 0.009, surviving the Bonferroni-corrected threshold of p < 0.0125), though this association was not replicated in PEARL-Neuro. Overall, these findings identify left fimbria volume as a localized structural correlate of APOE ε4 status that warrants further longitudinal and biomarker-confirmed evaluation.