Tuesday, April 16, 2024
4/16/2024
Abstract Alzheimer’s disease (AD) caused more than 110,000 deaths in 2017 making it the sixth most common cause of death. With an estimated lifetime risk of 40% in the U.S. population and an estimated cost of care exceeding $200 billion, ADRD is burdensome for individuals and their families, and costly to society. While work is increasingly determining risk and resilience factors for ADRD, little is known about causes of preclinical AD. Life course researchers have posited that a lifetime of stressors can accumulate to cause increased incidence of symptoms consistent with preclinical AD including changes to memory and early stages of cognitive impairment. In creating the first and only cognitive monitoring study of World Trade Center responders (R01 AG049953; PI, Clouston), we posited that chronic posttraumatic stress disorder (PTSD), a relatively common disorder characterized by intrusive memories of past trauma accompanied by a heightened stress response, might help to provide a unique mechanism linking lifetime stressors with later onset of cognitive decline reminiscent of ADRD. Those data sought to examine the extent to which childhood exposures, midlife exposures, genetic differences, and later-life changes in health would help to explain cognitive symptoms of preclinical AD in World Trade Center responders. While we now understand that PTSD predicts increased risk of cognitive and physical symptoms consistent with preclinical AD, the mechanisms of action for this association remain opaque. In a recent pilot study, we found that WTC responders have increased plasma neurofilament-light and plasma tau (which was associated with memory in this sample), and also identified a strong association between PTSD and changes to plasma amyloid-b burden. We now posit that PTSD may either cause an Alzheimer’s pathological cascade with one result being cognitive dysfunction in domains of fluid cognition including memory. This study seeks to examine, using longitudinal data, the extent to which PTSD might trigger an AD neuropathological cascade. However, since responders are very young to be experiencing ADRD, we additionally hypothesize that PSTD may reduce cognitive reserve thereby amplifying the effects of extant neuropathology. Finally, we propose an alternative hypothesis stating that inhaled nanoparticulate matter exposures, which some responders reported while at the WTC may have increased the burden of a known neurotoxin with one result being increased risk of neuropathological changes including increased tauopathy. !
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