Mapping Divergent Subfield-Specific Hippocampal Degeneration in Mild Cognitive Impairment Continuum: Volumetric, Cognitive, and Genetic Predictors of Accelerated Hippocampal Biological Aging

Abstract

Objective: To investigate hippocampal subfield atrophy and biological aging across the mild cognitive impairment (MCI) continuum, we used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI).

Methods: A cohort of 49 participants, categorized as cognitively normal (CN, n = 16), early MCI (EMCI, n = 16), or late MCI (LMCI, n = 17), underwent comprehensive neuroimaging, neuropsychological, and genetic assessments. High-resolution 3D T1-weighted MRI scans were processed using the volBrain platform and hippocampal subfield segmentation (HIPS) pipeline to quantify hippocampal subfield volumes and estimate biological age. Statistical analyses, including ANCOVA and stepwise regression, were employed to evaluate group differences and identify predictors of hippocampal biological age.

Results: The results revealed significant volumetric reductions in LMCI, particularly within the CA1, CA4/dentate gyrus (DG), and stratum radiatum/lacunosum/moleculare (SRLM) subfields, with pronounced lateralized effects. Clinical and demographic covariates attenuated group differences in biological age, but volumetric adjustments highlighted a significant distinction between EMCI and LMCI, with EMCI exhibiting a higher biological age. Cognitive performance, as measured by the Montreal Cognitive Assessment (MoCA), emerged as a consistent predictor of biological age, while APOE ε4 carrier status was significantly elevated in LMCI patients. Regression analyses identified divergent contributions of CA2/3 (positively associated) and CA4/DG (negatively associated) volumes to biological age, underscoring the subfield-specific pathophysiological mechanisms. Asymmetry indices, although variably expressed across groups, offered limited predictive utility, with CA2/3 and CA4/DG asymmetries modestly influencing biological age.

Conclusion: These findings support the integration of subfield-specific hippocampal volumetry and cognitive assessments in early diagnostic frameworks while highlighting the need for longitudinal studies to elucidate causal pathways linking subfield atrophy, biological aging, and cognitive decline.

Keywords: hippocampal biological age; mild cognitive impairment (MCI); neurodegeneration; neuroimaging; structural MRI.

FIGURE 1

Chronological age, hippocampal biological age, and subfield volumes across diagnostic groups: The left side represents chronological age alongside biological age estimates of the left and right hippocampus, stratified by diagnostic group (CN, cognitively normal; EMCI, early mild cognitive impairment; LMCI, late mild cognitive impairment). Numerical values represent individual participant data, with rows corresponding to chronological age, right hippocampal biological age, and left hippocampal biological age. On the right side, subfield volumetric data (CA1, CA2/3, CA4/dentate gyrus [DG], stratum radiatum/lacunosum/moleculare [SRLM], and subiculum) for the left and right hemispheres are displayed.

FIGURE 2

Education and clinical characteristics by the diagnostic group [Columns include years of education, Clinical Dementia Rating (CDR), Mini‐Mental State Examination (MMSE), and Montreal Cognitive Assessment (MoCA) scores. Rows are stratified by diagnostic group (CN, EMCI, LMCI)].

FIGURE 3

Left and right hippocampal subfield volumes. Volumetric data (cm³) for the left and right hippocampal subfields (CA1, CA2/3, CA4/DG, SRLM, subiculum). Each row corresponds to a participant, with the stack total representing the overall volume.

FIGURE 4

Hippocampal subfield volumetric comparisons by hemisphere and diagnostic group. The stacked row chart compares mean hippocampal subfield volumes (cm³) between left and right hemispheres across diagnostic groups (CN, EMCI, LMCI). Subfields include CA1, CA2/3, CA4/DG, SRLM, and subiculum. Each row corresponds to a participant, with the stack total representing the overall volume.

FIGURE 5

Hippocampal subfield asymmetry indices. The asymmetry indices (%), calculated as [(Right Volume − Left Volume)/Total Volume] × 100, for hippocampal subfields (CA1, CA2/3, CA4/DG, SRLM, and subiculum). Positive values represent rightward asymmetry, while negative values represent leftward asymmetry.