Plasma glial fibrillary acidic protein mediated the association of midlife pulmonary function and cognition in later‐life: A causal mediation analysis in a longitudinal population‐based cohort

Abstract

AbstractBackgroundEpidemiological evidence indicates that poorer pulmonary function (PF) may be linked to faster cognitive decline and a greater risk of dementia. Inflammation is one possible mediator between poor PF and cognitive decline. Plasma glial fibrillary acidic protein (GFAP,) as a marker of neurodegeneration and inflammation, may mediate the association of poor PF to poor cognitive function. The APOE ε4 is a marker of Alzheimer’s disease (AD) genetic susceptibility and may modify the PF‐cognition association with mediating factors. We aimed to prospectively examine whether GFAP mediates the association of mid‐life PF with cognition and whether the mediation effects differ by APOE ε4 carriership.MethodWe studied 1,001 participants (average midlife age of 50.5 years, 45% men) in the Age, Gene/Environment Susceptibility‐Reykjavik Study with midlife PF measures [forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC)] and blood draw and cognition measured on average 23 years later. Plasma GFAP levels were assayed using a Simoa HD‐1 analyzer. A general cognition score was created by principle component analysis using multiple cognitive tests. Causal mediation regression models were constructed to estimate GFAP’s mediation effect on the association between mid‐life PF and cognitive function in later life. Analyses were stratified by APOE ε4 status (yes/no). Models were adjusted for age, sex, education, smoking, BMI, and estimated glomerular filtration rate.ResultLow midlife FEV1 and FVC were related to poor general cognition in later life [β = 0.44 (95% CI = 0.28, 0.62) and β = 0.38 (95% CI = 0.22, 0.54), respectively]. Higher PF was associated with lower plasma GFAP levels. The proportion of the association between FEV1 on cognition mediated by plasma GFAP was 4.4% (95% CI = 1.0%–10.0%), and between FVC and cognition was 4.9% (95% CI = 0.8%–14.6%). The mediation effect was greater in the APOE‐ε4 allele carriers [14.4% (95% CI = 0.04%–60.9%) and 14.6% (95% CI = 1.0%–54.5%) for FEV1 and FVC, respectively].ConclusionLow PF in midlife may increase the risk for later cognitive problems. This study suggests poor PF may contribute to neuroinflammation (as measured by GFAP) over the long term, especially in individuals at genetic risk of AD.