Monocyte inflammation and resilience to Alzheimer’s disease: novel genetic risk genes identified by transcriptome-wide association study

Inflammation is a key driver of Alzheimer's disease (AD) and may connect all known AD risk factors. Recently, AD resilience outcomes have been developed which have helped to uncover mechanisms that enable some individuals to withstand significant AD pathology or genetic risk, while retaining cognitive function. We conducted a series of transcriptome-wide association studies (TWAS) focusing on monocytes, key innate immune cells that respond to pathogens and invade the CNS. Monocyte expression data under various immune stimulation states (naive, LPS 2 h, LPS 24 h, IFN 24 h) and corresponding genotype data from 432 individuals (Fairfax et al. [1]) were analyzed. We developed cis-genetic expression models using both elastic-net, and MASH combined with LD-pruning; capturing polygenic structures and independent inflammatory eQTLs across conditions, respectively. These models were applied to GWAS summary statistics of three AD resilience phenotypes: cognitive and global AD-resilience, and Amish cognitive preservation. We identified 180 TWAS results surpassing a suggestive significance threshold of PFDR < 0.20, including 92 unique genes. APP, a well-known AD gene, showed the strongest overall association, which may inform ongoing efforts targeting its action in the brain. Whole-blood RNA-seq data from a separate AD cohort confirmed differential expression between AD cases and controls in 35 putative targets, including: SURF1, ACKR3, LILRA5, FBXO2, ITPR1, and HRH4. We also demonstrate that the regulation of these genes is specific to monocytes. Finally, in-silico cell sorting (CIBERSORTx) revealed differential monocyte abundance by AD status, supporting monocyte-driven inflammation as a distinct, complementary pathway of myeloid cell involvement in AD. Together, these findings highlight monocytes as a critical and understudied cellular component for AD resilience mechanisms, with potential implications for novel immunotherapeutic strategies and precision medicine approaches in AD.