Similarities and differences between Alzheimer's disease and schizophrenia: drug target Mendelian randomization and transcriptome analysis

Background: Alzheimer’s disease (AD) and schizophrenia (SZ) are two complex neuropsychiatric disorders characterized by significant cognitive impairment. The relationship between them is complex and multifaceted. Understanding these similarities and differences is crucial for identifying common therapeutic targets.

Methods: Genetic data on plasma proteome were obtained from Icelandic datasets. Genetic variants associated with circulating inflammatory proteins, rheumatoid arthritis (RA) and AD and SZ, were sourced from large GWAS datasets. Mendelian randomization analyses were performed, and transcriptome analysis were applied to confirm the finding.

Results: We observed an association between the genetic loci of the AD and SZ traits (p < 0.05) by Linkage Disequilibrium Score Regression. Furthermore, our analysis indicates that RA has a protective effect against AD (OR: 0.36, p = 0.005) while potentially increasing the risk for SZ (OR: 2.49, p = 2.06 × 10⁻⁷). Among the 1,729 proteins analyzed, 16 proteins exhibited significant inverse causal relationships with AD and positive causal relationships with SZ. Notably, DECR2 emerged as a potential therapeutic target, showing opposing effects in AD and SZ as revealed by SMR analysis and colocalization.Conclusions: This study identifies causal proteins linked to AD and SZ, enhancing the understanding of their molecular etiology and supporting targeted therapeutics development.