Blood gene expression network expression strongly relates to brain amyloid burden

Area of Science:

• Neuroscience
• Genomics
• Immunology

Background:

• Amyloid deposition in Alzheimer's disease (AD) precedes clinical symptoms by decades.
• Identifying early biomarkers is crucial for understanding preclinical AD.
• Blood-based biomarkers offer a less invasive approach to assess brain pathology.

Purpose of the Study:

• To identify blood gene networks associated with brain amyloid burden in cognitively unimpaired individuals.
• To explore the relationship between blood transcriptomics and amyloid positron emission tomography (PET) measures.
• To find potential blood biomarkers for preclinical Alzheimer's disease.

Main Methods:

• Utilized whole-blood RNA sequencing and amyloid PET data from 1739 participants in the A4 study.
• Employed linear regression to correlate gene module expression with amyloid PET measures.
• Controlled for age, sex, and apolipoprotein E (APOE) genotypes in the analysis.

Main Results:

• A histone gene cluster module on chromosome 6 was significantly associated with lower brain amyloid levels (β = -0.55, FDR-adjusted p = 0.029).
• Key genes within this module included H1-5, H3C3, H2BC3, H2AC14, and RRM2, with H1-5 acting as a hub gene.
• Higher proportions of activated natural killer (NK) cells and CD4+ activated memory T cells were nominally associated with reduced amyloid deposition.

Conclusions:

• Blood-based gene expression, specifically involving histone genes on chromosome 6, serves as a correlate for brain amyloid deposition in preclinical AD.
• Immune cell proportions, including NK and CD4+ T cells, are implicated as potential blood biomarkers for amyloid pathology.
• These findings highlight the potential of blood transcriptomics and immune cell analysis for early detection and monitoring of Alzheimer's disease.