A transcriptome association study of AD risk genes in the pathogenesis of Alzheimer’s disease

Background Alzheimer’s disease (AD) affects millions of people with no effective treatments making it vital to identify potential therapeutic targets. Genome-wide association studies (GWAS) have consistently identified AD susceptibility loci or ‘hits’. Few these are differentially expressed in brain transcriptomic studies, meaning that their effects may be manifest via interacting downstream transcripts. We recently used machine learning on human data and validate an between lactoferrin amyloid (1). Here we apply the same method transcripts associated ‘loci’. Method Analyses were performed disease-linked genes from our analyses (LTF, ADAMTS2, PPDPF, PRTN3) combined 58 GWAS risk two recent (2, 3). Boruta was find each ‘hit’ interest pathologically confirmed cohorts (Religious Orders Study Memory Aging project, Mount Sinai Brain Bank). The hits correlated markers (cognition, plaque number, Braak score, CERAD score) direct indirect effects. Results TREM2 most both but ‘hits’ either not negatively markers. Among ‘hit’-associated transcripts, SWAP70, EMP3, WWTR1 positively VGF cohorts. For interest, ADAMTS2 PPDPF shared overlaps ABCA7. LTF linked plaques Conclusion This study has teased apart nascent associations known gene expression brain, also hints consideration pathological sub-phenotypes required make greater progress understanding pathogenesis. 1. Tsatsanis et al. acute phase protein is a key feature …. Mol Psychiatry. 2021;26(10):5516-31. 2. Yang A vascular atlas reveals diverse cell mediators risk. BioRxiv [Preprint]. 2021. 3. Wightman 1,126,563 individuals identifies new for disease. Nat Genet. 2021;53(9):1276-82.