A systems biology-based identification and in vivo functional screening of Alzheimer’s disease risk genes reveals modulators of memory function

Genome-wide association studies (GWAS) have uncovered over 40 genomic loci associated with risk for late-onset Alzheimer’s Disease (LOAD), but identification of the underlying causal genes remains challenging. While the role of glial biology in the mediation of LOAD genetic risk has been increasingly recognized, recent studies of induced pluripotent stem cell (iPSC)-derived neurons from LOAD patients have demonstrated the existence of neuronal cell-intrinsic functional defects, absent interactions with other brain cell types or exposure to neurotoxic insults. Here, we searched for genetic contributions to neuronal dysfunction in LOAD pathobiology, using an integrative systems approach that incorporated multi-evidence-based gene-mapping and network analysis-based prioritization. We found widespread dysfunction in neuronal gene co-expression networks in the LOAD brain and identified synaptic and endolysosomal function as being specifically impacted by LOAD-associated genetic variation. A systematic perturbation screening of candidate risk genes in C. elegans revealed that neuronal knockdown of the LOAD risk gene orthologs vha-10 ( ATP6V1G2 ), cmd-1 ( CALM3 ), amph-1 ( BIN1 ), ephx-1 ( NGEF ), and pho-5 ( ACP2 ) significantly alters short/intermediate-term memory function, the cognitive domain affected earliest during LOAD progression. These results highlight the impact of LOAD risk genes on evolutionarily conserved memory function, as mediated through neuronal endosomal dysfunction, and identify new targets for further mechanistic interrogation. ### Competing Interest Statement The authors have declared no competing interest.