Pathway Analysis for Plasma β-Amyloid, Tau and Neurofilament Light (ATN) in World Trade Center Responders at Midlife

Introduction: World Trade Center (WTC) responders who aided in the search and rescue efforts are now at midlife, and evidence has demonstrated that many are experiencing early-onset cognitive impairment and are at risk of developing dementia, such as Alzheimer’s disease (AD). According to the recent NIA-AA framework, AD is characterized by a neuropathological cascade commencing with β-amyloid deposition (A), followed by tauopathy (T) and neurodegeneration (N). However, the ATN model has not been replicated utilizing recently validated plasma-based biomarkers, and the role of the Aβ₄₀ subtype in A is not well understood. This study examined plasma-based neuropathological markers of Aβ₄₂ and Aβ₄₀ for A, total tau for T, and NfL for N in a cohort of World Trade Center responders at midlife in order to determine the role for the two β-amyloid subtypes in the ATN model. Methods: Ultrasensitive Simoa technology was utilized to measure neuropathology in plasma collected from a consecutive clinical sample (n =398). Generalized structural equation modeling was utilized for modeling linkages between pathological markers. Model fit was utilized to determine proposed directions of association. Results: Our findings support the ATN neuropathological cascade model of AD and further identify an associative role for Aβ₄₀ in A as playing a central role linking T to N. A strong correlation was found between CI and age, and it was found that women may be at increased risk of elevated T levels, with plasma NfL levels higher in responders with CI. Notably, our model reported associations between: Aβ₄₂, CI and N; Aβ₄₀, T and N; T and CI; Aβ₄₂ and Aβ₄₀. Conclusions: The current ATN model of AD does not specify the subtype of β-amyloid to be considered, which may be overlooking the differential roles that these two subtypes serve in the pathogenesis of AD.