NEUROLOGY AND THERAPY

Kritikos M, Clouston SAP, Diminich ED, Deri Y, Yang X, Carr M, Gandy S, Sano M, Bromet EJ and Luft BJ.

 Neurol Ther 9, 159–171 (2020)

DOI: https://doi.org/10.1007/s40120-020-00189-1

Abstract

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.