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 aim to assess the associations between ILF and AD biomarkers and to determine whether these biomarkers mediate the relationship 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; 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. Impaired lung function (ILF) was defined as predicted PEF <80%. Multivariable regression examined associations between lung function and AD biomarkers; causal mediation analysis evaluated their role in linking lung function to 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, 225)). 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. NfL mediated 7.3% (p=0.01) of the total effect of ILF on dementia, while p-Tau 181 mediated 5% (p=0.05) of this association. Discussion: ILF was associated with elevated levels of neurodegeneration markers NfL and p-Tau 181, which partially mediated its relationship with dementia risk. These findings highlight the importance of monitoring blood protein biomarkers in individuals with impaired lung health to facilitate early interventions.