Using diffusion MRI to relate hippocampal subfield microstructure to delayed verbal memory in cognitively intact individuals at genetic risk for developing Alzheimer's disease

Intervention to delay the onset of Alzheimer's disease (AD) is an important treatment strategy but detecting at-risk individuals before significant disease progression remains challenging. This study evaluates the relationship between hippocampal microstructure and verbal cognition in cognitively intact older adults, focusing on the differences between APOΕ ε4 allele carriers and noncarriers. Participants ( n = 41 noncarriers, 33 carriers) over 60 years old (mean ± SD: carriers 71 ± 6.6; noncarriers 71 ± 6.4 years) underwent diffusion-weighted magnetic resonance imaging (dMRI) and volumetric assessments. We assessed hippocampal structure, including microstructure, using Neurite Orientation Dispersion and Density Imaging (NODDI), diffusion tensor imaging (DTI), and volumetric measures. Regression analyses examined the relationship between these hippocampal measures and verbal and visuospatial cognition, as evaluated by the Rey delayed recall tests, i.e., the Auditory Verbal Learning Test (AVLT) and Complex Figure Test (CFT), respectively. Results indicated that while volumetric data showed no significant findings, microstructural measures, particularly orientation dispersion (ODI) in the left subiculum, were positively associated with verbal recall in APOΕ ε4 carriers ( p = 0.0011; Bonferroni-corrected alpha = 0.005). These findings suggest that hippocampal microstructure, rather than volume, may provide insights into cognitive decline in individuals at genetic risk for AD. • Memory linked to left hippocampus microstructure in APOE ε4 carriers • No memory link found using standard MRI volume in any group • Hippocampal microstructure measures provide complementary information beyond subfield volume in characterizing AD genetic risk