Subjective cognitive concerns, APOE ε4, PTSD symptoms, and risk for dementia among older veterans
Authors: Neale Zoe E. , Fonda Jennifer R. , Miller Mark W. , Wolf Erika J. , Zhang Rui , Sherva Richard , Harrington Kelly M. , Merritt Victoria , Panizzon Matthew S. , Hauger Richard L. , Gaziano J. Michael ,   the VA Million Veteran Program, Muralidhar Sumitra , Moser Jennifer , Deen Jennifer E. , Tsao Philip S. , Muralidhar Sumitra , Hauser Elizabeth , Kilbourne Amy , Luoh Shiuh-Wen , Matheny Michael , Oslin Dave , Tsao Philip S. , Churby Lori , Whitbourne Stacey B. , Brewer Jessica V. , Shayan Shahpoor Alex , Selva Luis E. , Pyarajan Saiju , Cho Kelly , DuVall Scott L. , Brophy Mary T. , Tsao Philip S. , Stephens Brady , Argyres Dean P. , Assimes Themistocles L. , Hung Adriana , Kranzler Henry , Aguayo Samuel , Ahuja Sunil , Alexander Kathrina , Androulakis Xiao M. , Balasubramanian Prakash , Ballas Zuhair , Beckham Jean , Bhushan Sujata , Boyko Edward , Cohen David , Dellitalia Louis , Faulk L. Christine , Fayad Joseph , Fujii Daryl , Gappy Saib , Gesek Frank , Greco Jennifer , Godschalk Michael , Gress Todd W. , Gupta Samir , Gutierrez Salvador , Harley John , Hammer Kimberly , Hamner Mark , Hung Adriana , Hurley Robin , Iruvanti Pran , Jacono Frank , Jhala Darshana , Kinlay Scott , Klein Jon , Landry Michael , Liang Peter , Liangpunsakul Suthat , Lichy Jack , Mahan C. Scott , Marrache Ronnie , Mastorides Stephen , Mates Elisabeth , Mattocks Kristin , Meyer Paul , Moorman Jonathan , Morgan Timothy , Murdoch Maureen , Norton James , Okusaga Olaoluwa , Oursler Kris Ann , Palacio Ana , Poon Samuel , Potter Emily , Rauchman Michael , Servatius Richard , Sharma Satish , Smith River , Sriram Peruvemba , Strollo Patrick , Tandon Neeraj , Tsao Philip , Villareal Gerardo , Wallbom Agnes , Walsh Jessica , Wells John , Whittle Jeffrey , Whooley Mary , Williams Allison E. , Wilson Peter , Xu Junzhe , Yeh Shing Shing , Logue Mark W. 
Published: July 2024

Abstract
Background
Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are associated with self-reported problems with cognition as well as risk for Alzheimer’s disease and related dementias (ADRD). Overlapping symptom profiles observed in cognitive disorders, psychiatric disorders, and environmental exposures (e.g., head injury) can complicate the detection of early signs of ADRD. The interplay between PTSD, head injury, subjective (self-reported) cognitive concerns and genetic risk for ADRD is also not well understood, particularly in diverse ancestry groups.

Methods
Using data from the U.S. Department of Veterans Affairs (VA) Million Veteran Program (MVP), we examined the relationship between dementia risk factors (APOE ε4, PTSD, TBI) and subjective cognitive concerns (SCC) measured in individuals of European (n = 140,921), African (n = 15,788), and Hispanic (n = 8,064) ancestry (EA, AA, and HA, respectively). We then used data from the VA electronic medical record to perform a retrospective survival analysis evaluating PTSD, TBI, APOE ε4, and SCC and their associations with risk of conversion to ADRD in Veterans aged 65 and older.

Results
PTSD symptoms (B = 0.50–0.52, p < 1E-250) and probable TBI (B = 0.05–0.19, p = 1.51E-07 – 0.002) were positively associated with SCC across all three ancestry groups. APOE ε4 was associated with greater SCC in EA Veterans aged 65 and older (B = 0.037, p = 1.88E-12). Results of Cox models indicated that PTSD symptoms (hazard ratio [HR] = 1.13–1.21), APOE ε4 (HR = 1.73–2.05) and SCC (HR = 1.18–1.37) were positively associated with risk for ADRD across all three ancestry groups. In the EA group, probable TBI also contributed to increased risk of ADRD (HR = 1.18).

Conclusions
The findings underscore the value of SCC as an indicator of ADRD risk in Veterans 65 and older when considered in conjunction with other influential genetic, clinical, and demographic risk factors.