Associations of peripheral inflammation with hippocampal atrophy in Alzheimer's disease

Peripheral inflammation has been implicated in Alzheimer's disease (AD), yet its links to hippocampal neurodegeneration and clinical progression remain incompletely defined. This study investigated associations of peripheral inflammatory markers with hippocampal volume fraction (HVF) and cognitive outcomes, alongside potential intermediary pathways. We included 320 participants (mean age 74.9 ± 6.9 years; 58.8% male) spanning cognitively unimpaired, mild cognitive impairment and AD individuals from the Alzheimer's Disease Neuroimaging Initiative. Peripheral inflammation was quantified using the neutrophils to lymphocytes ratio (NLR), platelet to lymphocytes ratio (PLR), and systemic immune-inflammation index (SII). We evaluated their cross-sectional associations with HVF, Aβ, tau and cerebrospinal fluid central inflammatory markers. Linear mixed-effects models characterized longitudinal HVF and cognitive trajectories, and Cox regression modelled clinical progression. Consequently, higher peripheral inflammatory markers correlated with reduced HVF (β = -0.12 to -0.17, q < 0.05). Mediation analyses indicated peripheral inflammatory burden may serve as an intermediary pathway linking APOE ε4-related genetic susceptibility to HVF. Longitudinally, higher baseline PLR and SII were associated with faster HVF decline, whereas no significant associations were observed with longitudinal cognitive trajectories. In an exploratory subgroup restricted to cognitively normal participants, the median SII tertile was tentatively associated with subsequent progression to MCI or AD (HR = 3.09, p = 0.02). Peripheral inflammatory markers showed no associations with Aβ, tau, or central inflammatory markers. These results support a link between systemic inflammatory burden and hippocampal vulnerability, while relationships with AD pathology and clinical progression warrant further investigation.