DNA methylation patterns contribute to changes of cellular differentiation pathways in leukocytes with LOY from patients with Alzheimer''s disease

Alzheimers disease (AD) is a common and increasing societal problem due to the extending human lifespan. In males, loss of chromosome Y (LOY) in leukocytes is strongly associated with AD. We studied here DNA methylation and RNA expression in sorted monocytes and granulocytes with and without LOY from male AD patients. Through multi-omic analysis, we identified new candidate genes and confirmed the involvement of numerous genes previously associated with AD. Our findings highlight LOY-related differences in DNA methylation that occur in gene regulatory regions and are predominantly accompanied by down-regulation of affected genes. Specifically, we observed alterations in key genes involved in leukocyte differentiation: FLI1, involved in early hematopoiesis; RUNX1, essential for blood cell development; RARA, regulating gene expression in response to retinoic acid; CANX, crucial for protein folding; CEBPB, a transcription factor important for immune responses; and MYADM, implicated in cell adhesion and migration. Moreover, protein-protein interaction analysis in granulocytes identified that products of two of these genes, CANX and CEBPB, are key hub proteins. Thus, LOY appears to dysregulate genes involved in leukocyte differentiation and induce higher-level epigenetic changes. This research underscores the potential of multi-omic approaches in pure cell populations to uncover the molecular underpinnings of AD and reinforces the significance of LOY as a pathogenic factor in this disease. Overall, results support the hypothesis that age-related immune cell dysfunction contributes to AD development. Finally, our results link previous analysis showing impact of LOY on leukocyte differentiation, LOY-associated transcriptional dysregulation and GWAS studies of LOY.