Neuropathology-based GWAS for Alzheimer's disease reveals novel susceptibility loci and highlights sex-specific pathways

Dementia refers to an umbrella phenotype of many different underlying pathologies with Alzheimers disease (AD) being the most common type. While Genome-wide Association Studies (GWAS) of clinically defined AD have identified multiple AD susceptibility variants, a significant portion of the heritability remains unexplained highlighting the phenotypic and genetic heterogeneity of the clinically defined entity. Furthermore, despite womens increased susceptibility to dementia there is a lack of sex-specific genetic studies and understanding of sex-specific background for the disorder. Here, we aim to tackle the heterogeneity of AD by specifically concentrating on neuropathological features which are the gold standard for diagnosis and pursuing sex-specific analysis. We bring together 13 different genomic and neuropathology datasets (6,960 individuals) and we integrate our GWAS findings with transcriptomic and proteomic data (ROSMAP and Mayo studies) aiming to also identify in vivo biomarkers for AD progression. We uncover novel genetic associations to AD neuropathology, including BIN1, OPCML, and CDH4. Our sex-specific analysis points to a role for BIN1 specifically in women as well as novel AD loci including QRFPR and SGCZ. Tissue-specific associations in females, particularly in the ovary issue, suggest a connection between sex hormones and AD. Finally, we pursue the identification of in-vivo biomarkers associated with AD neuropathology, with a goal to offer insights into disease progression and potential therapeutic targets. Our findings contribute to unraveling the molecular basis of AD, emphasizing the importance of sex-specific analyses and multi-omics approaches. Further research is needed to validate and explore the clinical utility of these findings.