RNASE6 is a novel modifier of APOE-ε4 effects on cognition.

Apolipoprotein E4 (APOE-ε4), the strongest common genetic risk factor for Alzheimer's disease (AD), contributes to worse cognition in older adults. However, many APOE-ε4 carriers remain cognitively normal throughout life, suggesting that neuroprotective factors may be present in these individuals. In this study, we leverage whole-blood RNA sequencing (RNAseq) from 324 older adults to identify genetic modifiers of APOE-ε4 effects on cognition. Expression of RNASE6 interacted with APOE-ε4 status (p = 4.35 × 10-8) whereby higher RNASE6 expression was associated with worse memory at baseline among APOE-ε4 carriers. This interaction was replicated using RNAseq data from the prefrontal cortex in an independent dataset (N = 535; p = 0.002), suggesting the peripheral effect of RNASE6 is also present in brain tissue. RNASE6 encodes an antimicrobial peptide involved in innate immune response and has been previously observed in a gene co-expression network module with other AD-related inflammatory genes, including TREM2 and MS4A. Together, these data implicate neuroinflammation in cognitive decline, and suggest that innate immune signaling may be detectable in blood and confer differential susceptibility to AD depending on APOE-ε4.