Sex‐specific molecular profiling to understand pathology and identify causal genes and drug targets for Alzheimer’s disease

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is a highly heterogeneous multifactorial disease. Genetic influences on AD are strong as shown by several pathogenic genes and over 50 AD GWAS loci. There are also clear sex differences in AD risk and progression. Women are at a higher risk of developing AD and present faster progression. A recent GTEx study also highlights sex differences in the genetic regulation of gene expression. Despite these established sex differences, sex‐specific molecular findings in AD are still limited.MethodWe generated and performed analysis using 713 CSF proteomic data that passed QC obtained from Knight‐ADRC and DIAN samples. The sample includes 190 late onset clinical AD patients and 509 age‐ and gender‐matched cognitively healthy individuals. Age at lumbar puncture and surrogate variables (to account for unmeasured heterogeneity) were included as covariates. To evaluate sex‐specific molecular signatures, we performed sex‐stratified analysis by separately analyzing 333 males and 366 females.ResultIn male CSF tissues, 99 proteins significantly associated with late onset AD status (FDR P < 0.05) and 131 proteins in female CSF tissues. Those proteins were enriched in pathways involved in the endolysosome and proteasome pathway including HSP70. We identified 44 proteins presenting a suggestive evidence of sex‐specific effects on AD status. In particular, several proteins that were previously reported to be associated with AD risk show sex‐specific effects. Downregulation of LRIG3 improves cognitive impairment and alleviate neuronal damage in hippocampus tissues in AD rats through modulating the PI3K/Akt pathway. We found that LRIG3 was associated in males only and would not have been identified through a combined analysis that simply included sex as a covariate (P = 3.4×10‐3 in males; P > 0.5 in females; P = 0.067 in all).ConclusionThis study demonstrates that 800 proteins in 700 CSF tissues can provide a suggestive information on sex‐specific proteomic profiles. We will extend our sex‐specific analysis using our recently generated 7000 proteomic data to fully understand the biology of the disease and determine the role of sex in disease, create sex‐specific genes and prediction models. This will provides insights for clinically translatable interventions for prevention and treatment.