Military‐related risk factors for dementia

Abstract

INTRODUCTION: In recent years, there has been growing discussion to better understand the pathophysiological mechanisms of traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) and how they may be linked to an increased risk of neurodegenerative diseases including Alzheimer’s disease (AD) in veterans. METHODS: Building on that discussion, and subsequent to a special issue of Alzheimer's & Dementia published in June, 2014, which focused on military risk factors, the Alzheimer's Association convened a continued discussion of the scientific community on December 1, 2016. RESULTS: During this meeting, participants presented and evaluated progress made since 2012 and identified outstanding knowledge gaps regarding factors that may impact veterans’ risk for later life dementia. DISCUSSION: The following is a summary of the invited presentations and moderated discussions of both the review of scientific understanding and identification of gaps to inform further investigations.

Psychological Stress–Induced Immune Response and Risk of Alzheimer's Disease in Veterans from Operation Enduring Freedom and Operation Iraqi Freedom

“…This study reports that chronic stress is clearly a risk factor for developing AD and dementia. 9, 58,59 TBIs, with or without PTSD, can increase tau deposition in the brain in veterans. 60 PTSD and TBIs are strongly associated with neurocognitive dysfunction in OIF veterans.…”

Association between military service and Alzheimer's disease neuropathology at autopsy

“…Military service as a determinant of AD neuropathology may operate broadly and distally, for example, as a marker of chronic stress risk stemming from psychological factors and chronic physical pain. [10][11][12][13][14][15][16][17][18][19][20][21][22] It may also operate more proximally and specifically as determinants tied to conditions and contexts that have lasting consequences, for example, when there is exposure to physical trauma (eg, traumatic brain injuries) and environmental hazards (Agent Orange). 10,14,16,[22][23][24] The military exposome may also expose individuals to a unique set of heightened exposures to AD risks after service (eg, cardiovascular risk factors).…”

“…The impact of the military exposome on AD risk can be conceptualized and researched in several ways. Military service as a determinant of AD neuropathology may operate broadly and distally, for example, as a marker of chronic stress risk stemming from psychological factors and chronic physical pain 10–22 . It may also operate more proximally and specifically as determinants tied to conditions and contexts that have lasting consequences, for example, when there is exposure to physical trauma (eg, traumatic brain injuries) and environmental hazards (Agent Orange) 10,14,16,22–24 .…”

Chronic traumatic encephalopathy: Diagnostic updates and advances

“…TREM2 is also expressed in the microglia of the brain, regulating microglial activation and playing a multi-faceted role in its immune response [102] , [103] . Animal studies have shown that TREM2 is upregulated in the early stages following injury, making it a potential biomarker for TBI and other head injuries [104] . When microglia in the brain are activated, following injury, cleavage of TREM2 by proteases follows.…”

“…Therefore, elevated levels of sTREM2 are non-specific. Because upregulation of TREM2 begins early and persists over time [104] , it could prove to be a key inflammatory marker used for the diagnosis of CTE in the appropriate clinical context.…”