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. 2022 Oct:118:66-76.
doi: 10.1016/j.neurobiolaging.2022.06.011. Epub 2022 Jul 1.

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

Mabel Seto  1 , Rebecca L Weiner  1 , Logan Dumitrescu  2 , Emily R Mahoney  2 , Shania L Hansen  2 , Vaibhav Janve  2 , Omair A Khan  3 , Dandan Liu  3 , Yanling Wang  4 , Vilas Menon  5 , Philip L De Jager  6 , Julie A Schneider  4 , David A Bennett  4 , Katherine A Gifford  7 , Angela L Jefferson  7 , Timothy J Hohman  8
Affiliations

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

Mabel Seto et al. Neurobiol Aging. 2022 Oct.

Abstract

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.

Keywords: Alzheimer's; Blood; Brain; Cognition; Gene expression.

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Conflict of interest statement

Conflicts of Interest The authors report no conflicts of interest.

Figures

Fig. 1.
Fig. 1.. APOE-ε4 allele carriers in VMAP have worse baseline cognition in the presence of higher levels of RNASE6 expression.
A) A scatterplot demonstrating how RNASE6 expression modifies the association between APOE-ε4 positivity and cognitive performance (β=−1.16, p=4.35x10−8). Baseline composite memory scores are denoted on the y-axis; and the x-axis represents quantile normalized and batch controlled RNASE6 expression in whole blood. Points and lines are colored by APOE-ε4 positivity where APOE-ε4 carriers are denoted by the color red. B) Baseline executive function scores are denoted on the y-axis. APOE-ε4 carriers expressing higher levels of RNASE6 also have worse baseline executive function (β=−0.54, p=0.008). C) A scatterplot including only individuals with normal cognition (β=−0.58, p=0.007). D) A scatterplot including only individuals with MCI (β=−0.87, p=0.002).
Fig. 2.
Fig. 2.. Amyloid and tau positivity drives poorer cognitive performance at baseline
A) A scatterplot demonstrating how RNASE6 expression modifies the association between amyloid positivity and baseline memory. Amyloid-positive individuals expressing higher levels of RNASE6 have worse baseline memory than individuals who are not amyloid-positive (β=−1.14, p=0.001). Baseline composite memory scores are denoted on the y-axis; and the x-axis represents quantile normalized and batch controlled RNASE6 expression in whole blood. Points and lines are colored by amyloid positivity where amyloid positivity is denoted by the color red. B) Tau-positive individuals expressing higher levels of RNASE6 also have worse baseline memory than individuals who are not tau-positive (β=−0.63, p=0.04).
Fig. 3.
Fig. 3.. CSF biomarker levels are modulated by RNASE6 expression.
A) Brain amyloid burden is reduced in APOE-ε4 non-carriers when RNASE6 expression is high (β= 91.8, p=0.02). Baseline CSF Aβ1-42 levels are denoted on the y-axis and whole blood RNASE6 expression is on the x-axis. CSF Aβ1-42 levels have an inverse relationship with brain amyloid burden such that higher CSF Aβ1-42 is indicative of lower brain amyloid levels. B) In contrast, CSF tau levels increase as RNASE6 levels increase in APOE-ε4 carriers (β=230.1, p=0.003). C) CSF pTau levels also increase as RNASE6 levels increase in APOE-ε4 carriers (β=22.7, p=0.01). In all plots, CSF biomarker levels are denoted on the y-axis; and the x-axis represents quantile normalized and batch controlled RNASE6 expression in whole blood. Points and lines are colored by APOE-ε4 positivity where APOE-ε4 carriers are denoted by the color red.
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