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

ABSTRACT Rationale We hypothesize that impaired lung function contributes to dementia risk via biological mechanisms reflected in AD/ADRD-related protein biomarkers, and aim to evaluate their role in mediating this relationship. Methods Serum p-Tau181 and plasma Aβ42/40 ratio, 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 biennially from 2014–2020 to determine dementia status. Impaired lung function (ILF) was defined as PEF <80% predicted. 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. Conclusions 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.