Impaired lung function is associated with elevated blood biomarkers of AD/ADRD: unraveling the interplay with risk of dementia

Background and Objectives: Impaired lung function (ILF) has been associated with cognitive decline and dementia risk in multiple cohorts, yet the role of circulating Alzheimer disease (AD) biomarkers in this relationship is not well understood. We aimed to assess the associations of ILF with AD-related blood biomarkers and to evaluate whether these biomarkers statistically accounted for part of the observed association between ILF and incident dementia. Methods: Serum p-Tau181 and plasma Aβ42/40, NfL, and GFAP were measured in 4,072 participants (mean age 66 ± 10 years; 59% women) in the 2016 Health and Retirement Study. Peak Expiratory Flow (PEF) was assessed in 2012/2014, and cognitive function was measured at four time points between 2014 and 2020 (every two years) to determine dementia status. ILF was defined as predicted PEF < 80%. Multivariable regression examined associations between ILF and AD biomarkers. Mediation models were used to evaluate the extent to which biomarkers statistically accounted for the association between ILF and incident dementia. Results: In total, 881 (21.6%) participants had ILF and 272 (6.8%) participants developed dementia. After adjusting for demographics, education, BMI, smoking, comorbidities, inflammation, eGFR and APOE e4, ILF was associated with a higher risk of dementia (HR = 1.74; 95% CI (1.34, 2.25)). Individuals with ILF had 0.10 SD higher NfL (SE = 0.03; p = 0.004) and 0.09 SD higher p-Tau 181 (SE = 0.03; p = 0.002) compared to those without ILF. In mediation models, higher NfL and p Tau181 accounted for modest proportions of the observed association between ILF and incident dementia, with estimated mediated proportions of 7.3% for NfL and 4.9% for p Tau181. Discussion: ILF was associated with higher levels of blood biomarkers reflecting neurodegeneration and with increased risk of dementia. NfL and p-Tau181 accounted for modest proportions of this association in mediation analyses, suggesting a limited and exploratory contribution. These findings support further investigation into biological pathways linking lung function and cognitive decline.