LINKING DIABETES AND DEMENTIA RISK:A ROLE FOR Aβ-42 INDUCED ACTIVATION OF THE NLRP3 INFLAMMASOME? RESULTS FROM THE ENBIND STUDY

Abstract Ref: 
0085

Adam Dyer1,2,3 , Isabella Batten2,3 , Isabelle Killane4,5,ConorWoods6,7 , James Gibney6,7 ,
Desmond O’Neill1,3, Richard Reilly5,3 ,Nollaig Bourke2,3, Sean Kennelly1,3

1Department of Age-Related Healthcare, Tallaght University Hospital,Dublin, Ireland
2Trinity Translational Medicine Institute, Trinity College Dublin,Dublin, Ireland
3Department of Medical Gerontology, Trinity College Dublin, Dublin, Ireland
4Department of Engineering, Technological University Dublin,Dublin, Ireland
5Trinity Centre for Bioengineering, Trinity College Dublin,Dublin, Ireland
6Department of Endocrinology, Tallaght University Hospital,Dublin, Ireland
7School of Medicine, Trinity College Dublin, Dublin, Ireland

Background: Midlife Type 2 Diabetes Mellitus (T2DM) is associated with a greater
risk of dementia in later life. The innate immune NLRP3 inflammasome, an innate
immune receptor, has been implicated in both T2DM and Alzheimer’sDementia (AD) and
can become activated by Amyloid-β 42 (Aβ-42). We analysed inflammasome-dependent
cytokine responses in midlife T2DM and correlated these with cognitive and gait performance

Methods: Peripheral BloodMononuclearCells (PBMCs) of otherwise healthy patients with
T2DM (n=30; 52±8 yrs) and matched controls (n=15; 52.5±7.86 yrs) were incubated
for 18h with the following NLRP3 ligands: (i) Lipopolysaccharide (LPS), (ii) Aβ42 or
(ii) LPS & Aβ42. Cell supernatants were analysed for production of the inflammasomedependent
cytokine IL-1β. Cognitive function was assessed using the MoCA and gait
speed assessed under self-selected, maximal and cognitive dual-task conditions. Mann-
Whitney,Wilcoxon tests and linear regression of log-transformed data were used to analyse
results

Results: Incubation of PBMCs from all participants with NLRP3 agonists was associated
with significant production of IL-1β (all p<0.001). There were no statistically significant
between-group differences in IL-1β production. MoCA score did not predict IL-1β production
by PBMCs.However, poorer performance on the cognitive dual-task gait paradigm
was associated with significantly greater IL-1β production in response to LPS & Aβ42
in those with T2DM (p=0.015), which persisted after robust control for demographic,
cognitive and cardiovascular covariates (p=0.003). The same association was not seen for
healthy controls (p=0.58).

Conclusion: Both LPS&Aβ42 induce significant IL-1β production in PBMCs which did
not differ between those with midlife T2DM and healthy controls. Poorer performance
on the cognitive dual task gait paradigm was associated with significantly greater IL-1β
production in response to LPS & Aβ42. Given the value of dual task gait in predicting
cognitive decline, longitudinal follow up of this cohort may provide insight into the
underlying pathophysiological mechanisms and potential biomarkers of dementia risk in
T2DM.