Plasma Amyloid Beta 40/42, Phosphorylated Tau 181, and Neurofilament Light Are Associated with Cognitive Impairment and Neuropathological Changes among World Trade Center Responders: A Prospective Cohort Study of Exposures and Cognitive Aging at Midlife

IntroductionWorld Trade Center (WTC) responders are experiencing a high risk of mild cognitive impairment (MCI) and dementia, though the etiology remains inadequately characterized. This study investigated whether WTC exposures and chronic post-traumatic stress disorder (PTSD) were correlated with plasma biomarkers characteristic of Alzheimer's disease (AD) neuropathology. MethodsEligible participants included WTC-exposed individuals with a baseline cognitive assessment and available plasma sample. We examined levels of the amyloid beta (A beta)40/42 ratio, phosphorylated tau 181 (p-tau181), and neurofilament light chain (NfL) and associations with a WTC exposures (duration on site >= 15 weeks, dust cloud), the PTSD Symptom Checklist for Diagnostic and Statistical Manual of Mental Disorders, 4th edition PTSD, and classification of amyloid/tau/neurodegeneration (AT[N]) profiles. Multinomial logistic regressions assessed whether biomarkers predicted increased risk of MCI or dementia. ResultsOf 1179 eligible responders, 93.0% were male, mean (standard deviation) age 56.6 years (7.8). A beta 40/42, p-tau181, and NfL intercorrelated and increased with age. In subgroup analyses of responders with available neuroimaging data (n = 75), A beta 40/42 and p-tau181 were further associated with decreased hippocampal volume (Spearman's rho = -0.3). Overall, 58.08% of responders with dementia had >= 1 elevated biomarker, and 3.45% had elevations across all biomarkers. In total, 248 (21.05%) had MCI and 70 (5.94%) had dementia. Increased risk of dementia was associated with plasma AT(N) profile T+ or A+N+. Exposure on site >= 15 weeks was independently associated with T+ (adjusted risk ratio [aRR] = 1.03 [1.01-1.05], P = 0.009), and T+N+ profile (aRR = 2.34 [1.12-4.87]). The presence of PTSD was independently associated with risk of A+ (aRR = 1.77 [1.11-2.82]). DiscussionWTC exposures and chronic PTSD are associated with plasma biomarkers consistent with neurodegenerative disease.