Protein kinase C eta enhances Golgi-localized signaling and is associated with Alzheimer's disease using a recessive mode of inheritance.

The identification of Alzheimer's disease (AD)-associated genomic variants has provided powerful insight into disease etiology. Genome-wide association studies (GWAS) for AD have successfully identified new targets but have almost exclusively utilized additive genetic models. Here, we performed a family-based GWAS under a recessive inheritance model using whole genome sequencing from families affected by AD. We found that the variant, rs7161410, located in an intron of the PRKCH gene, encoding protein kinase C eta (PKCη), was associated with AD risk (p-value=1.41 × 10-7). Further analysis revealed a rare PRKCH missense mutation K65R in linkage disequilibrium with rs7161410, which was present in homozygous carriers of the rs7161410 risk allele. We show that this mutation leads to enhanced localization and signaling of PKCη at the Golgi. The novel genetically-validated association of aberrant PKCη signaling with AD opens avenues for new therapeutic targets aimed at prevention and treatment.