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VanGilder, Jennapher Lingo; Hooyman, Andrew; Hakhu, Sasha; Schilling, Kurt G.; Hu, Leland S.; Zhou, Yuxiang; Caselli, Richard J.; Baxter, Leslie C.; Beeman, Scott C. (2026).Ìý.ÌýExperimental Gerontology, 218, 113112.Ìý

This study explores how subtle changes in the brain may help identify people at risk for Alzheimer’s disease (AD) before symptoms appear. The researchers focused on the hippocampus, a brain region important for memory, and compared older adults who carry the APOE ε4 gene variant (a known genetic risk factor for AD) with those who do not. Using advanced brain imaging techniques, including diffusion MRI methods that examine the brain’s microstructure (the fine, internal organization of brain tissue), they looked at how these features relate to memory performance.

The results showed that overall hippocampal size did not differ in a meaningful way. However, more detailed microstructural measures—especially a metric called orientation dispersion (ODI), which reflects how nerve fibers are organized—were linked to better verbal memory performance in people with the APOE ε4 variant. In particular, higher ODI in a specific hippocampal subregion (the left subiculum) was associated with better recall of spoken information.

These findings suggest that looking at the brain’s microstructure, rather than just its size, may provide earlier and more sensitive clues about cognitive changes in people at genetic risk for Alzheimer’s disease.

Fig. 1.ÌýShown are the absolute values of log-transformed raw p-values for the APOE ε4 interaction across 10 hippocampal regions of interest (i.e., left and right CA1, CA2–3, CA4, subiculum, and whole hippocampus), assessed for ODI, NDI, FA, MD, and volumetric metrics in relation to CFT recall and AVLT scores. Higher the magnitudes on the graph correspond to smaller p-values. The dashed line represents the threshold for statistical significance after Bonferroni correction for 10 comparisons (p = 0.005). Notably, only the left subiculum was associated with AVLT, indicating significant interaction effects that persist beyond multiple comparison correction.