The Effect of APOE ε4 on Alzheimer's Disease Fluid Biomarkers: A Cross-Sectional Study Based on the COAST

Abstract

Aims: To analyze the effect of APOE ε4 on fluid biomarkers and the correlations between blood molecules and CSF biomarkers in AD patients.

Methods: This study enrolled 575 AD patients, 131 patients with non-AD dementia, and 112 cognitively normal (CN) participants, and AD patients were divided into APOE ε4 carriers and non-carriers. Cerebrospinal fluid (CSF) biomarkers and blood-derived biomolecules were compared between AD and CN groups, between non-AD dementia and CN groups, as well as within APOE ε4 subgroups of AD patients. Utilizing Spearman's correlation analysis and quantile regression analysis, the relationships between blood-derived biomolecules and CSF biomarkers were analyzed in APOE ε4 carriers and non-carriers.

Results: The levels of CSF biomarkers and blood molecules exhibited significant differences between the AD and CN groups, including Aβ42, t-tau, p-tau 181, high-density lipoprotein, low-density lipoprotein (LDL), and uric acid. In AD patients, APOE ε4 carriers had increased levels of CSF t-tau, p-tau 181, and plasma LDL. In the correlation and regression analyses, the negative relationships between plasma TG and t-tau, between plasma TG and p-tau 181 levels, as well as the positive relationship between serum IgA and CSF Aβ42, were observed significantly in APOE ε4+ AD groups, but not in APOE ε4- AD group.

Conclusion: APOE ε4 is associated with accelerated progression of AD pathology. The blood-derived biomolecules correlated with CSF biomarkers in APOE ε4 carriers are related to neuroinflammation and lipid metabolism, which may indicate the role of APOE ε4 in AD pathophysiology and offer insights for diagnostic and therapeutic strategies for AD.

Trial registration: ClinicalTrials.gov identifier: NCT03653156.

Keywords: Alzheimer's disease; apolipoprotein E; biomarker; high‐density lipoprotein; immunoglobulin; low‐density lipoprotein; uric acid.

FIGURE 1

Study design. The patients with non‐AD dementia included patients with frontotemporal dementia, Parkinson's Disease dementia, and Lewy Body dementia. The other diseases which could affect cognitive assessment included corticobasal degeneration, multiple sclerosis, substance abuse, severe systematic diseases, active infections, chronic wasting disease, autoimmune diseases, hematological system diseases, newly onset cardiovascular diseases, stroke, and traumatic brain injury. In AD patients, the APOE ε4 carriers were matched with the non‐carriers by age, sex, and educational level. AD, Alzheimer's disease; APOE, apolipoprotein E; CN, cognitively normal; COAST, China Cognition and Aging Study.

FIGURE 2

Differences of CSF biomarkers and blood biomolecules between the groups of CN, AD, and non‐ADD. All p values were adjusted by Benjamini/Hochberg (B/H) method. Aβ, amyloid‐beta; AD, Alzheimer's disease; CN, cognitively normal; CSF, cerebrospinal fluid; C3, complement C3; HDL, high‐density lipoprotein; IgA, Immunoglobulin A; LDL, low‐density lipoprotein; non‐ADD, non‐AD dementia; p‐tau, phosphorylated tau; TG, triglycerides; t‐tau, total tau; UA, uric acid. *B/H adjusted p < 0.05, **B/H adjusted p < 0.01, ***B/H adjusted p < 0.01.

FIGURE 3

Differences of CSF biomarkers and blood biomolecules between the APOE ε4‐ and APOE ε4+ groups in AD patients. Aβ, amyloid‐beta; AD, Alzheimer's disease; APOE, apolipoprotein E; CSF, cerebrospinal fluid; C3, complement C3; HDL, high‐density lipoprotein; IgA, Immunoglobulin A; LDL, low‐density lipoprotein; p‐tau, phosphorylated tau; TG, triglycerides; t‐tau, total tau; UA, uric acid. *p < 0.05, **p < 0.01.

FIGURE 4

Heat maps of correlations between blood‐derived biomolecules and CSF biomarkers. Shown are the correlations between blood‐derived biomolecules and CSF biomarkers in all matched AD patients (A), APOE ε4+ AD patients (B), and APOE ε4− AD patients (C). All p values were adjusted by Benjamini/Hochberg (B/H) method. Aβ, amyloid‐beta; AD, Alzheimer's disease; APOE, apolipoprotein E; CSF, cerebrospinal fluid; C3, complement C3; HDL, high‐density lipoprotein; IgA, Immunoglobulin A; LDL, low‐density lipoprotein; p‐tau, phosphorylated tau; TG, triglycerides; t‐tau, total tau; UA, uric acid. *B/H adjusted p < 0.05, **B/H adjusted p < 0.01, ***B/H adjusted p < 0.001.

FIGURE 5

Associations between blood‐derived molecules and CSF biomarkers in APOE subgroups of AD patients. Utilizing the quantile regression method (at 0.50 quantile), shown are the relationships between serum IgA and CSF Aβ42 levels in APOE ε4 carriers (A), between plasma TG and CSF t‐tau levels in APOE ε4 carriers (B), between plasma TG and CSF p‐tau 181 levels in APOE ε4 carriers (C), between plasma HDL and CSF p‐tau 181 levels in APOE ε4 non‐carriers (D), and between plasma TG and CSF p‐tau 181 levels in APOE ε4 non‐carriers (E). All models were adjusted for age, sex, education level, and disease duration. All p values were adjusted by Benjamini/Hochberg (B/H) method. Aβ, amyloid‐beta; AD, Alzheimer's disease; APOE, apolipoprotein E; CSF, cerebrospinal fluid; HDL, high‐density lipoprotein; IgA, Immunoglobulin A; p‐tau, phosphorylated tau; TG, triglycerides; t‐tau, total tau.