Background: Memory loss commonly reflects hippocampal compromise and may rise from neurodegeneration, neuroinflammation and Alzheimer’s disease (AD) pathology. Blood-based biomarkers now enable the detection of these processes non-invasively; however, the pathways linking these biomarkers to memory impairment and hippocampal integrity remain unclear, particularly in at-risk populations. This study examined whether hippocampal subfields mediate associations between blood-based biomarkers and verbal memory performance in older adults at-risk for AD. We also investigated whether these associations differed between individuals with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). 

Methods: The sample included 263 older adults at-risk for AD aged >50 years (mean age=68.79; 71% female) recruited from a specialist memory clinic. All participants underwent fasting blood collection, MRI scanning, and comprehensive neuropsychological assessment. Volumes of CA1, subiculum, and dentate gyrus were extracted from structural MRI scans. Plasma phosphorylated tau 217 (pTau217), amyloid-β 42/40, glial fibrillary acidic protein and neurofilament light chain (NfL) were measured using the SIMOA HD-X platform, while serum YKL-40 was quantified using ELISA. Mediation analyses, adjusted for age, sex, BMI, and APOE ε4, were conducted in the full sample and separately in SCD and MCI subgroups.

Results: CA1 volume fully mediated the association between NfL and verbal memory (b=−.008, 95% CI [−.0160, −.0004]). For pTau217, CA1 partially mediated the relationship with verbal memory (b=−.085, 95% CI [−.1845, −.0074]). In the MCI subgroup, mediation patterns for NfL and pTau217 showed similar direction and magnitude but did not reach significance, likely due to reduced power. No other mediation effects were observed.

Conclusions: These findings suggest that CA1 volume mediates key biomarker–memory relationships in older adults at-risk for AD. CA1 acted as a structural pathway linking NfL to memory decline, while pTau217 showed both hippocampal and extra-hippocampal effects.Integrating blood-based and imaging markers may strengthen early risk prediction and inform targeted interventions.