Dementia is a degenerative disease of the brain that is expected to affect as many as 40% of the U.S. population 1, 2. Although dementia is an uncommonly devastating disease, milder prodromal forms of cognitive impairment (CI) are more common and also implicate substantial losses in cognitive functioning 3. Risk factors for CI and dementia include age, smoking, alcohol intake, cardiovascular disease, education, diabetes, and depression 4. Research suggests that post‐traumatic stress disorder (PTSD) may also be associated with reduced cognitive functioning and increased risk of dementia 5, 6. PTSD involves complex memory, emotional, and behavioral processes 7, and encompasses distinct domains including re‐experiencing, effortful avoidance, emotional numbing, and hyperarousal resulting from a traumatic event 8. Exact mechanisms for this association remain understudied 9. Theories suggest, on the one hand, that PTSD may be a unique part of the causal pathway leading to CI 10. However, the association may be confounded by co‐morbid features that are independently associated with PTSD and dementia, such as traumatic brain injury 11. Finally, symptoms indicative of PTSD, which is commonly comorbid with major depressive disorder (MDD) 12, may be manifestations of CI and dementia 13. It is thus unclear whether reported associations between PTSD and cognitive impairments and dementia are due to reverse causation.

Thousands of responders who helped in search, rescue, and cleanup efforts after the World Trade Center (WTC) were exposed to an extraordinary array of psychological traumas and toxic exposures. Although few were physically injured by their efforts, many responders witnessed the disaster or death and dismemberment of others, helped civilians flee, lost colleagues in the tower collapse, and dug through debris to search for survivors 14 . Since then, researchers examining WTC responders have found high rates of chronic PTSD. Yet, the potential effects of persistent mental health symptoms on CI have not been examined 15 .

Hypotheses and data structure for the Stony Brook University World Trade Center Aging Study 2002–2015. (A) Hypothesized progression of cognitive and non‐cognitive changes. Solid lines, charted on the left y‐axis, reflect changes in cognition whereas dashed lines, charted on the right y‐axis, reflect changes in non‐cognitive mental health symptoms. (B) Structure of the longitudinal PTSD sample and cross‐sectional cognitive sample. Enrollment is open, and some patients have left. WTC exposures precede data collection, but mental health symptoms have been gathered since 2002, and diagnoses and cognitive screening were done concurrently in 2014–2015.

Based on existing studies, we hypothesized that current WTC‐PTSD will be associated with CI. Dementia researchers largely agree that CI is generally characterized as undergoing a period of accelerated decline before becoming diagnostic ( Fig. 1 A) 16 , 17 . We posited that such change might also be observed in noncognitive outcomes, such as via increasing depressive symptoms (dashed line), in a way similar to cognitive outcomes. Thus, longitudinal analyses of depressive and PTSD symptoms before cognitive screening may help interpret concurrent associations. Specifically, changes in related noncognitive factors could be used to help mark the course of the disease. If so, then reverse causation would be evident by significantly increasing symptoms before screening positive for CI. In contrast, risk factors may be those that, alternatively, precede the course of the disease and/or are not subject to such reverse causal effects.

Law enforcement officers differ from other responders with respect to exposures, extent of disaster training, and burden of PTSD. Similarly, those with pre‐WTC head injuries may differ from those without. Analyses were stratified to examine whether results differed across these subpopulations; Chow test was used to test whether differences were significant. For clarity, analyses further examined whether excluding individuals enrolled in the study after 2010 modified results. Longitudinal analyses also examined any changes to conclusions when modifying distributional assumptions, including examining negative binomial, ordinal, and logistic regression specifications. Similarly, analyses examined whether conclusions drawn from trajectory analyses changed when limited to individuals with at least three observations. Analyses examined whether excluding those screening positive for possible dementia (MoCA<18) changed conclusions, and further multinomial logistic regression was used to jointly examine conclusions predicting both CI and dementia. Because treatment may provide a mechanism through which PTSD affects CI, analyses examined whether treatment for PTSD‐mediated results.

Multivariable logistic regression was used to examine the potential for diagnoses of PTSD and MDD to predict CI, and subdomains of PTSD identified as robust to reverse causation in predicting CI. The risk of CI was not rare in this sample so odds ratios will overestimate the relative risk. Multivariable‐adjusted risk ratios (aRRs) were derived from logistic regression using the Muller and MacLehose 29 risk ratio.

PTSD/MDD symptom growth could be interpreted as indicative of reverse causation resulting from early noncognitive changes in mental health accompanying CI and may thus help us to chart the course of the disease and identify whether PTSD preceded or may have resulted from CI. Associations that are consistent and predate such reverse causation may then be interpretable as risk factors for CI. Descriptive analyses thus examined trajectories of symptom change for responders with and without current CI. Longitudinal multivariate models were used to examine symptom change leading up to cognitive assessments 27 . Models integrated individual‐level random intercepts to account for unobserved heterogeneity in baseline symptomatology. Random slopes estimate individual‐specific growth and account for heteroskedasticity common in growth models 28 . Enrollment date was used to model temporal change in sample selection; temporal metrics were centered in the observational window. Using an unstructured covariance, matrix further accounted for associations between baseline capability and change over time. To facilitate comprehension, graphical trajectories were provided. The 813 responders provided 7.24 (SD = 2.95) person‐years of data collected during 3995 clinic visits from 2002–2014. Analyses were implemented in Stata 14.1/IC.

Descriptive sample statistics provide means and standard deviations, as well as percentages. Sample characteristics were also reported separately for those with and without CI. T tests were used to compare continuous variables between groups; χ 2 tests were used to provide P values for dichotomous predictors.

Trauma severity was assessed at enrollment using a structured history. Two measures of exposure were included: early arrival (arrived on 9/11 and were caught in the dust cloud or saw human remains) and chronic exposure (responders who worked at least 7 days in September 2001 digging through debris).

Predisposing characteristics were included. Education improves cognitive reserve 23 ; because >98% of responders had at least a high‐school degree, education were categorized into those with some college, those completing a bachelor's degree, versus those with less education. Occupation was dichotomized into law enforcement (the majority at SBU) versus nontraditional responders (e.g., construction or utility workers). Pre‐WTC PTSD was assessed using the SCID. Pre‐WTC history of head injury was coded as none, previous loss of consciousness, concussion, or multiple head injuries.

PTSD symptoms were assessed at each monitoring visit using the PTSD checklist, specific trauma version tailored to the WTC disaster (PCL‐17 trauma specific version) 21 . Individuals rated the extent to which they were bothered by 17 DSM‐IV WTC‐related PTSD symptoms in the past month on a scale from 1 (not at all) to 5 (extremely). Items were summed within four PTSD symptom dimensions consistent with four‐factor models of PTSD dimensionality 8 : re‐experiencing the event (e.g., flashbacks/nightmares), effortful avoidance (e.g., actively avoiding reminders), emotional numbing (e.g., emotionally distancing from life), and hyperarousal (e.g., being ever aware and on edge). Depressive symptoms were measured using the Patient Health Questionnaire (PHQ‐9) 22 . PHQ‐9 items, rated on a scale from 0–3 over the past 2 weeks, were summed in a standard way to provide a total score. For comparative purposes, both scales were transformed to range from 0 (no symptomatology) to 1 (maximal observed symptomatology). Baseline symptomatology refers to symptomatology collected during a responder's first clinic visit.

Trained psychologists administered the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders‐IV to diagnose both PTSD and MDD 20 . Inter‐rater agreement was high (κ = 0.82) among 55 independent ratings. To facilitate rapport and interpretation, interviewers were tasked with reviewing participant's histories before assessments. The PTSD module used WTC exposures as the index trauma. Both current (i.e., active in the past month) and remitted (i.e., not active in the past month) diagnoses were analyzed. Treatment for PTSD is freely available in the clinic to responders in need; 70.8% of those categorized as having current PTSD and 43.3% of those with remitted PTSD received treatment for PTSD.

Trained clinicians administered the Montreal Cognitive Assessment (MoCA) starting February 2014. The MoCA consists of multiple short‐form neuropsychological tests that are scored in a standard way. A relatively conservative cutoff score of <23 was used to indicate CI, and a score of <18 was used to suggest possible dementia. These cutoffs have been shown to have >95% sensitivity and specificity in community‐dwelling older adults 18 . Presence of the apolipoprotein‐ε4 ( APOE ) has been strongly associated with the risk for Alzheimer's disease 19 . APOE status was measured using polymerase chain reaction on blood banked in a subsample of these responders (n = 593).

Trained clinicians screened responders for CI during monitoring visits at the SBU clinics starting in 2014. Of those approached, 89.8% completed the screening, 0.6% did not complete due to extenuating circumstances, 0.4% only finished part of the screening, and 8.7% refused to participate in this cognitive screening. Those who refused testing did not differ in terms of PTSD ( P = .165), WTC exposures ( P = .940), educational attainment ( P = .580), or law enforcement status ( P = .105) from those who completed testing. On average, SBU responders were aged 52.8 years when this sample was taken. A total of 818 Responders with valid diagnostic information were eligible for this study. To assess exclusion bias, 128 responders screened using a different PTSD diagnostic tool were also screened for CI. Data were linked to existing monitoring records that included PTSD and depressive symptoms measured obtained serially since baseline ( Fig. 1 B). Five responders who reported any head injury obtained on‐site were excluded, leaving an analytic sample of 813 responders. Clinic visit date was recorded.

In July 2002, the Centers for Disease Control and Prevention initiated a monitoring and treatment program for WTC responders, spanning five clinical centers. Since then, more than 33,000 responders have enrolled in the WTC Health Program and form the WTC general responders cohort 14 . Stony Brook University (SBU) runs the second largest clinical center, monitoring >8000 responders residing on Long Island, NY. SBU's population had similar exposures to the general responder cohort and was similar in age on 9/11/2001 (38.7 in the WTC general responder cohort versus 38.4 at SBU) 14 . However, the SBU population includes relatively more law enforcement personnel and men and fewer individuals without a high‐school degree. The SBU Institutional Review Board approved this study, and responders provided written informed consent; >95% of responders consented for data to be used for research purposes.

Bivariate analyses showed no association between enrollment year and the odds of CI, and longitudinal analyses show no association between enrollment year and PTSD. Stratifying analyses by enrollment year, law enforcement status, head injury status, and omitting those with possible dementia did not alter conclusions. Further stratifying by age of responder provided similar results. Multinomial logistic regression results adjusting for age rely on small numbers ( eTable 3 ) but revealed strong independent associations between re‐experiencing and both CI (RR = 3.94 [1.53–10.17]) and dementia (RR = 17.45 [1.10–275.69]). Longitudinal results were robust using different distributional assumptions. Examining exclusion bias, prevalence in a sample of responders who were ineligible for this study (n = 128) showed similar prevalence of CI (12.5% vs. 12.8% above, difference = 0.3%, P = .925). APOE ε4/ε4 was associated with increased risk of possible dementia (RR = 9.68 [1.13–83.11]). Adjusting for medications did not decrease the size of the association between diagnosed PTSD and CI (to 1.83 from 1.92) but attenuated its significance.

Because longitudinal analyses indicated that re‐experiencing symptom severity may be a risk factor for CI, adjusted analyses were used to examine the robustness of this domain in predicting CI ( Table 3 ). Re‐experiencing symptom severity ranged from 0 to 1 and average 0.17 (SD = 0.20) in general and ranged from 0.16 (SD = 0.19) in those not screening positive for CI to 0.23 (SD = 0.23) among those who screened positive for CI. Adjusting for predisposing factors (model 1) showed a significant association between age and CI. Accounting for WTC exposures (model 2) and for health factors including treatment for PTSD and baseline depressive symptoms (Model 3) did not improve model fit (model 2, P = .654; model 3, P = .406). Notably, baseline re‐experiencing symptom severity predicted diagnoses of remitted and current PTSD and MDD ( eTable 2 ).

The lack of association between current, but not remitted, diagnoses might be indicative of a potential for longitudinal symptom growth. Indeed, longitudinal analyses ( Fig. 2 B–E) suggested that baseline levels of avoidance, hyperarousal, numbing, and depressive symptoms were not associated with CI. Instead, longitudinal analyses revealed that symptoms increased more rapidly (by ∼0.9%/year) among responders with current CI. In contrast, for re‐experiencing symptoms, longitudinal analyses suggest consistent associations with CI beginning as early as 2002 that did not change with time ( Fig. 2 A).

Diagnoses were associated with CI after accounting for covariates. Indeed, Table 2 revealed that current PTSD remained significantly associated with CI after adjusting for predisposing, WTC exposures, and for health and behavioral mediators (model 1). Adjusted analyses also found that current MDD remained associated with CI (model 2).

As shown in Table 1 , 104 of 813 (12.8%) responders had any CI, of whom 10 (1.2% of 813) had probable dementia. Bivariable analyses ( Table 1 ) showed that responders with CI had lower education, nontraditional occupations, older age and were more likely to be current smokers than those without CI. Current WTC‐PTSD and MDD were both associated with CI, as was receiving treatment for PTSD.

5 Discussion

This study examined the extent of CI among WTC responders and associations between CI and WTC‐PTSD/MDD in a sample of 813 WTC responders without WTC‐related head injury. Approximately one in seven (12.8%) of sampled SBU WTC responders screened positive with CI, whereas 1.2% had possible dementia. If representative of actual prevalence of CI in the general responder cohort (N∼33,000) 14, results may translate into 3740–5300 and 240–810 with CI and dementia respectively in that patient population. These numbers are staggering, considering that the average age of responders was 53 during this study. Future research is needed to diagnose, and clarify determinants of, CI in this population.

Current, but not remitted, WTC‐PTSD and MDD were associated with a two‐fold increase in CI. Longitudinal analyses highlight growth in a number of symptom domains, including avoidance, numbing, hyperarousal, and depressive symptoms among those who later screen positive for CI. Such growth may indicate early manifestations of CI. Strikingly, analyses suggested that re‐experiencing symptoms were consistently associated with CI (aRR = 2.88, 95% CI = 1.35–6.22), irrespective of observational period. To our knowledge, this is the first study to examine the association of PTSD and MDD with CI and to do so in a civilian sample of WTC responders without concurrent head trauma.

5.1 Limitations Results require validation using comprehensive batteries of cognition and diagnostic evaluations by a trained clinician to diagnose the cause of CI found here to ensure that WTC‐CI is not a unique disease and that discussed are not spurious. Such analyses should start by examining domain‐specific factors and longitudinal declines in cognitive functioning. Although CI and dementia were associated with APOE status, replicating earlier analyses 19, APOE was not associated with risk of PTSD in these data nor did APOE status modify the association between exposure and PTSD. Results are limited to participants who were selected for screening, and this study does not inform us about the relative risk of WTC responders to other individuals with similar occupational exposures. Although a separate sample of SBU responders who were ineligible for this study revealed similar prevalence (12.5% with CI), efforts may seek to improve generalizability by gathering prospective data from cognitively normal WTC responders and from nonexposed controls to determine incidence of CI. Finally, although four WTC responders with WTC‐related head injury were excluded, one‐third of the sample reported some history of head trauma including loss of consciousness or concussion often due to sports injuries or car accidents. Although no significant association was found linking head injuries and CI, future research should explore whether specific aspects of prior head injury (e.g., age of first occurrence, number of injuries) may modify the relationship between PTSD and CI.

5.2 Aging Traumatic stress can arise from various sources ranging from natural and human‐made disasters to interpersonal traumas. Approximately 5%–10% of individuals exposed to trauma develop chronic PTSD 30. In a primary care sample aged 65 years and older, 24% reported some lifetime trauma, and one third of them (8% of patients) had symptoms consistent with PTSD 31. Few studies of survivors of, or responders to, disasters have considered the potential impact of PTSD on CI and the reverse 15. Indeed, a lone longitudinal study of PTSD symptom change in relation to memory (n = 28) found inconsistent results 32, although a large study of veterans found that PTSD was associated with a two‐fold increase in the risk of incident dementia 33. The present study revealed that experiencing trauma resulting in PTSD is associated with increased risk of CI, thereby extending results from Veterans studies to a civilian sample while highlighting the importance of monitoring cognitive functioning in traumatized populations.

5.3 Neurodegeneration Dementia results from several causes including neurodegeneration resulting in CI 34. The prodromal period is usually characterized by accelerated cognitive aging, which can last a decade 35, and increasing levels of CI in the years before becoming diagnostic for dementia 16. Milder forms of CI are the largest risk factor for incident dementia and are thus often called prodromal 34, 36. The prodromal period can be accompanied by noncognitive behavioral and emotional changes 37. For example, one prospective study of incident dementia found that the risk of depression increased among previously nondepressed respondents during the prodromal period suggesting that depression has the potential to act as an early manifestation or risk indicator of dementia 38. Our study analyzed changes in PTSD and depressive symptoms measured routinely across over a decade before cognitive screening and found that depressive and many PTSD symptoms were no different in 2002 between those with and without CI and increased only in those who later screened positive for CI. Yet, whereas results for most symptom domains suggested that changes in PTSD and depressive symptoms may be part of the prodrome of CI, associations between re‐experiencing symptoms and CI uniquely lead to a different set of conclusions, namely that they preceded the onset of CI and were not subject to reverse causation.

5.4 Post‐traumatic stress disorder Common treatments for PTSD include cognitive behavioral therapy and pharmacological treatments, notably selective serotonin reuptake inhibitors 39. Currently, 70.8% of responders with current PTSD are being treated, making this study underpowered to examine the potential role of medications versus diagnoses. Nevertheless, studies suggest that cognitive deficits are not evident with common PTSD treatments 40. Moreover, in sensitivity analyses, the association between re‐experiencing symptoms, which are insufficient for diagnosis alone, and CI remained even after adjusting for medications, suggesting that re‐experiencing symptoms and not medications were attributable for lowered cognitive performance. Results support research noting the importance of re‐experiencing symptoms as an early marker of mental pathology 7. Intrusive re‐experiencing symptoms are the embodiment of a neurological flash bulb memory processes, which can be triggered by stressful events and tend to remain consistent for many individuals 41 that are a foundational element of chronic PTSD. Re‐experiencing symptoms occur when individuals react physically and emotionally to memories of past trauma that intrude during daily activities and while asleep. Sleep disturbances are fundamental to PTSD 42, may exacerbate allostatic load 43, and have been linked to incident dementia 44. However, intrusive stress while awake has also been previously associated with poorer episodic memory 45 and poorer fluid cognition 46, potentially highlighting the central importance of cognitive interference to CI. Evidence linking such complex memory and behavioral processes to CI could be interpreted in several ways. Re‐experiencing traumatic events could cause CI, possibly through a number of plausible biological mechanisms including increased allostatic load 10. If so, efforts to prevent or treat PTSD may have long‐term benefits. Re‐experiencing symptoms may be part of the PTSD syndrome, with chronic PTSD linked to risk of CI, in which case diagnostic efforts may benefit from cognitive screening. Alternatively, those at risk of re‐experiencing the event may be similarly vulnerable to CI in some unobserved fashion. Further research is needed to examine whether broken sleep cycles are a mechanism linking PTSD to CI.