Microstructural Changes in Aging Hippocampal Pathways: Insights From the HCP-Aging Diffusion MRI Study

While hippocampal atrophy in Alzheimer's disease is well-documented, research on microstructural integrity of hippocampal pathways to selected cortical regions in healthy aging populations remains limited. Four hundred seventy-five healthy individuals aged 36–90 from the Human Connectome Project Aging (HCP-A) dataset were analyzed. Hippocampal fiber pathways, including the “Papez,” “Prefrontal,” “Occipital,” and “Parietal” pathways, were extracted from whole-brain tractography and characterized by fractional anisotropy (FA) and mean diffusivity (MD), neurite density index (NDI), and orientation distribution index (ODI). Partial linear and quadratic nonlinear correlation analyses were conducted to examine the relationship between age, cognition, and diffusion metrics, adjusted by hippocampus volumes. While FA, MD, and ODI demonstrated linear age-related changes, NDI exhibited a quadratic pattern. MD was identified as the most age-sensitive parameter. Among all pathways, the “Prefrontal” pathway showed the most pronounced microstructural changes in both males and females, characterized by reduced FA and NDI and increased MD and ODI with age (FA: r = −0.31 to −0.40; NDI: r² = 0.30–0.31; MD/ODI: r = 0.23–0.48; p < 0.01). Similar changes were observed in the “Occipital” pathway (FA: r = −0.28 to −0.39; MD/ODI: r = 0.32–0.50; p < 0.01), with NDI reduction present only in females (r² = 0.18, p < 0.01). In the “Parietal” pathway, changes were detected only in females, with lower FA (r = −0.29, p < 0.01) and higher ODI (r = 0.24, p < 0.01). Additionally, age-related cognitive decline was significantly associated with microstructural changes in the “Occipital” (FA: r = 0.29; MD: r = −0.28; ODI: r = −0.25; p < 0.001) and “Prefrontal” pathways (FA: r = 0.27; MD: r = −0.25; NDI: r = 0.25; ODI: r = −0.22; p < 0.01) in females. This study revealed age- and cognition-related changes in hippocampal pathways across the adult lifespan. These findings provide normative references for hippocampal-cortical connectivity changes associated with healthy aging and its potential relevance to Alzheimer's disease and related dementias.