Plasma Immune Markers Associated with Hippocampal Volume in The Northern Manhattan Study

BACKGROUND & METHODS

• Hippocampal atrophy is an early biomarker of Alzheimer's disease and accelerated brain aging.
• Peripheral inflammatory molecules may inform structural brain health.
• Prior immune marker studies have been limited by small marker panels and ethnically homogeneous or clinical samples.

Objective: To identify plasma immune markers associated with age-related total hippocampal volume on MRI through large-scale immune profiling in a multiethnic, urban-dwelling Northern Manhattan Study (NOMAS) cohort.

Methods:
Population: MRI NOMAS subcohort; stroke-free, dementia-free; aged ≥50
Outcomes:
1. HV: log-transformed ratio of total hippocampal volumes (L and R) to total cranial volume (TCV) on T2-MRI;
2. Age-standardized HV: HV residualized for age (z-score)
Exposure: Concentrations of 60 plasma immune-related molecules via multiplex immunoassay (Luminex).
Statistics: Data reduction (LASSO regression) selected candidate markers. Selected markers were modeled in quartiles using multivariable linear regression.
Adjustment: Global vascular risk score which incorporates demographic, clinical, and lifestyle factors and APOE ε4

RESULTS

N=815 | Age 70±9 | 60% female | 67% Hispanic | 68% HTN | 30% smoker | 19% depression

Mean HV 7.29 ± 0.9 mL; Mean HV/TCV: 0.6% ± 0.08%

Data reduction selected:
● GM-CSF ● CXCL9 ● IL-4

In fully-adjusted analysis:

1. Granulocyte-macrophage colony stimulating factor (GM-CSF; CSF2)
• Each quartile increase in GM-CSF ~ 0.14 SD larger age-standardized HV (95% CI 0.08–0.20)
• Greater GM-CSF quartiles (Q3 & Q4 vs. Q1) ~ greater HV, and ↑ HV than expected for age (plot).
2. C-X-C motif chemokine ligand 9 (CXCL9; MIG)
• Each quartile increase in CXCL9 ~ 0.02 SD smaller HV (95% CI −0.03, −0.01)
• CXCL9 Q4 (vs. Q1) ~ −3.5% lower HV (β = −0.06; 95% CI −0.09, −0.02)
3. Interleukin-4 (IL-4)
IL-4 showed no significant association with HV across quartiles.

CONCLUSIONS:

• GM-CSF showed a dose-dependent association with larger hippocampal volume relative to age-expected values, suggesting a possible neuroprotective effect.
• Higher CXCL9 levels showed a graded association with smaller HV (more atrophy). The association with age-standardized HV was directionally consistent but did not reach statistical significance.
• Immune-related markers may inform subclinical gray matter biological processes relevant for future mechanistic studies and therapeutic interventions.