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. !

Public Health Relevance

The events of September 11th, 2001 traumatized many of the men and women who aided in rescue and recovery operations at Ground Zero were exposed to an extraordinary array of stressful experiences. In 2014, we began the only cognitive monitoring study of World Trade Center responders and have since identified associations between WTC exposures and cognitive symptoms consistent with preclinical Alzheimer?s disease. In this renewal application, we propose to build on our existing research framework to examine the extent to which PTSD instigates changes in blood-based biomarkers indicative of an Alzheimer?s disease neuropathological cascade.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG049953-06A1
Application #
10050057
Study Section
Neurological, Aging and Musculoskeletal Epidemiology (NAME)
Program Officer
Roberts, Luci
Project Start
2015-05-15
Project End
2025-04-30
Budget Start
2020-09-15
Budget End
2021-04-30
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
State University New York Stony Brook
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
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Clouston, Sean A P; Shapira, Oren; Kotov, Roman et al. (2017) Proton pump inhibitors and the risk of severe cognitive impairment: The role of posttraumatic stress disorder. Alzheimers Dement (N Y) 3:579-583
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Clouston, Sean; Pietrzak, Robert H; Kotov, Roman et al. (2017) Traumatic exposures, posttraumatic stress disorder, and cognitive functioning in World Trade Center responders. Alzheimers Dement (N Y) 3:593-602
McGrath, John J; Saha, Sukanta; Al-Hamzawi, Ali et al. (2016) The Bidirectional Associations Between Psychotic Experiences and DSM-IV Mental Disorders. Am J Psychiatry 173:997-1006
McGrath, John J; Saha, Sukanta; Al-Hamzawi, Ali O et al. (2016) Age of Onset and Lifetime Projected Risk of Psychotic Experiences: Cross-National Data From the World Mental Health Survey. Schizophr Bull 42:933-41
Clouston, Sean A P; Glymour, Maria; Terrera, Graciela Muñiz (2015) Educational inequalities in aging-related declines in fluid cognition and the onset of cognitive pathology. Alzheimers Dement (Amst) 1:303-310