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WHOLE-BLOOD RNA SEQUENCING DETECTS CHANGES IN THE PERIPHERAL BLOOD TRANSCRIPTOME IN PRECLINICAL ALZHEIMER’S DISEASE
Abstract
Aims
We investigate longitudinal changes in peripheral blood gene expression to better understand molecular changes in preclinical Alzheimer’s disease (AD).
Methods
RNA was extracted and sequenced from whole-blood for 63 cognitively healthy Flemish Prevent AD Cohort KU Leuven (F-PACK) participants (70 (56-80) years) at baseline and follow-up (interval: 4.6 (3.4-8.59) years). Participants also received amyloid-PET and structural MRI at both timepoints. We performed differential gene expression analysis to identify changes in expression of single genes, based on APOE4 status (present/absent) and amyloid rate of change. Results were significant when meeting FDR<0.05 and log fold change (LFC)±1.
Results
There were 121 differentially expressed genes (DEGs) at follow-up compared to baseline in APOE4 carriers. Top differentially expressed genes (DEGs) included GP1BA (FDR=0.003, LFC=-2.70) and RPL17 (FDR=0.003, LFC=2.13). Over-representation analysis revealed DEGs were particularly enriched for gene ontology terms related to structural constituents of ribosomes and endoplasmic reticulum function. No significant DEGs were observed in APOE4 non-carriers between baseline and follow-up. There was only one gene, ZFAT, that was differentially expressed at baseline with respect to amyloid rate of change (FDR=0.002, LFC=20.2). However, the significance appears to be driven by one individual with a particularly high accumulation rate, Figure 1A. Significance is lost when this individual is removed (FDR=0.99, Figure 1B).
Conclusions
Early peripheral blood-related RNA expression changes occur in relation to AD genetic risk factors (APOE4), as well as early brain amyloid changes. These results may aid in targeting genes or pathways for biomarker development or finding druggable targets for AD.