Few serum proteins mediate APOE's association with dementia

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• The apolipoprotein E (APOE) e4 allele is a significant risk factor for dementia.
• Cognitive impairment involves a latent variable, delta (δ), specifically linked to dementia.
• Understanding the mechanisms linking APOE e4 to dementia is crucial for developing interventions.

Purpose of the Study:

• To investigate serum proteins as mediators of the association between APOE e4 and delta (δ) in a diverse cohort.
• To explore the specific pathways through which APOE e4 influences cognitive decline.

Main Methods:

• Analysis of a large, ethnically diverse longitudinal cohort (Texas Alzheimer's Research and Care Consortium - TARCC).
• Examined associations between APOE genotype, serum proteins (CRP, Adiponectin, Amphiregulin), and delta (δ).
• Statistical analysis including Bonferroni correction for multiple comparisons.

Main Results:

• APOE e4 was specifically associated with C-Reactive Protein (CRP), Adiponectin (APN), and Amphiregulin (AREG).
• CRP, APN, and AREG were all associated with delta (δ).
• Weak mediation effects of these proteins on the APOE e4-δ association were observed, with most of the effect remaining unexplained.

Conclusions:

• APOE's association with cognitive performance is specific to the dementia-related component (δ) and partially mediated by serum inflammatory proteins.
• The majority of APOE's effect on δ is not explained by these serum proteins, suggesting potential direct central nervous system effects.
• APOE may exert a lifelong influence on dementia risk, potentially impacting cognitive abilities from early life.