Elevated lipopolysaccharide binding protein in Alzheimer's disease patients with APOE3/E3 but not APOE3/E4 genotype

Alzheimer's DiseaseAPOE genotypeBlood-Brain BarrierCognitive Declineendotoxemia

Elevated lipopolysaccharide binding protein in Alzheimer’s disease patients with APOE3/E3 but not APOE3/E4 genotype

Why this matters for your gut health

Gut permeability and the leakage of bacterial endotoxins (LPS) into circulation is increasingly linked to chronic inflammation and diseases like Alzheimer’s. However, no prior study had examined whether the strongest known genetic risk factor for Alzheimer’s — APOE genotype — changes this gut-permeability/AD relationship. Understanding this is critical because APOE4 carriers already have 4–12x higher genetic risk, while APOE3/E3 carriers (lower genetic risk) may develop AD through different pathways, such as gut-derived inflammation. If LBP-driven inflammation is a distinct AD pathway in APOE3/E3 individuals, it points to a modifiable, diet/lifestyle-based risk factor for this subgroup.

Summary

Researchers measured lipopolysaccharide binding protein (LBP), a marker of gut permeability and bacterial endotoxin exposure, in the 1.21–1.25 g/mL density fraction of plasma (enriched in intestinally-derived HDL) from 79 participants: APOE3/E3 carriers (20 with AD, 20 controls) and APOE3/E4 carriers (19 with AD, 20 controls). LBP concentrations were measured via ELISA and correlated with cognitive and clinical outcomes.

Key findings

LBP was significantly enriched in the 1.21–1.25 g/mL density fraction of plasma (linked to intestinally-derived HDL).
Overall, AD patients had significantly higher LBP index than controls (0.96 vs. 1.57, p=0.018), though significance weakened after adjusting for covariates (p=0.147).
When stratified by APOE genotype: APOE3/E3 AD patients had significantly higher LBP than APOE3/E3 controls (0.82 vs. 1.83), significant even after adjustment (p=0.049).
No significant LBP difference was found between APOE3/E4 AD patients and controls (p=0.815 unadjusted, p=0.565 adjusted).
LBP index was negatively correlated with Verbal Memory Score (R=−0.42, p<0.001) and positively correlated with Clinical Dementia Rating sum of boxes (R=0.37, p=0.002).
No significant association was found between LBP and white matter hyperintensities volume.
Findings suggest gut permeability/endotoxemia may be a more critical driver of AD specifically in genetically low-risk (APOE3/E3) individuals, rather than in APOE4 carriers where genetic risk may dominate.

Read the full paper

VIEW PDF

Citation

Romo EZ, Hong BV, Patel RY, Agus JK, Harvey DJ, Maezawa I, Jin L-W, Lebrilla CB, Zivkovic AM (2024). Elevated lipopolysaccharide binding protein in Alzheimer’s disease patients with APOE3/E3 but not APOE3/E4 genotype. Front. Neurol. 15:1408220. doi: 10.3389/fneur.2024.1408220