No Evidence of Connection Between Traumatic Brain Injury, PTSD and Elevated Alzheimer-Related Biomarkers

Michael Weiner, MD

Data from a recently published study in Alzheimer’s & Dementia showed no association between increased levels of Alzheimer disease (AD)-related biomarkers and veterans exposed to traumatic brain injury (TBI) and/or posttraumatic stress disorder (PSTD). Patients with TBI, PTSD, and/or both demonstrated poorer cognitive status; however, investigators believed that may have been attributable to other comorbid pathologies.

Led by Michael Weiner, MD, professor of radiology, University of California, San Francisco, the study included 289 nondemented veterans with either PSTD (n = 81), TBI (n = 43), or TBI and PTSD (n = 93), as well as controls (n = 71) who were followed up for up to 5.2 years. Each patient underwent clinical evaluation, cerebrospinal fluid (CSF) collection, MRI, amyloid-ß and tau PET, and apolipoprotein ε testing.

Controls were demographically comparable and service-connected for conditions other than TBI-related injuries or PTSD, and had no record of TBI or PTSD before, during, or after the Vietnam War (1955-1975). Demographically, there was a difference in frequency of mild cognitive impairment (MCI) among the groups, with each of the exposure groups associated with higher frequency of MCI than of controls (P <.001). Additionally, the number of errors on the Mini-Mental State Examination (MMSE) differed between the groups (P = .03), with PTSD (P = .008) and both TBI and PTSD (P = .009) groups having more errors than control group, both of which remained significant after Tukey-Kramer adjustment for multiple comparisons.

Despite no AD-related biomarker changes, the poorer cognitive performance from those with TBI and/or PTSD, "raises questions about alternative mechanisms underlying cognitive symptoms and AD diagnosis in these patients," Weiner et al wrote.

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Besides MMSE, there were no significant between-group differences in any other cognitive scores. Furthermore, there were no significant differences in florbetapir or flortaucipir standard reuptake ratio nor in regional MRI volumes, white matter hyperintensity volume, and CSF biomarkers available for a subset of patients.

Longitudinal cognitive/functional assessments, obtained over an average of 1.8 years (standard deviation [SD], 1.1) in a subset of patients, showed no significant differences between groups except for Clinical Dementia Rating-Sum of Boxes, which worsened more in the TBI group than in controls. On longitudinal MRI, the difference in annual rates of change across groups did not reach significance, nor were there any significant differences in rate of change in flortaucipir PET SUVR (P >.30) in a limited effect, small-sample model. Notably, among cognitively unimpaired veterans aged at least 65 years with 12 years of education and no APOE ε alleles, hippocampal volume significantly declined only in the TBI group by 0.01% (standard error, 0.004; P = .004).

In an additional analysis of 49 participants with MCI with TBI, PTSD, and TBI+PTSD were compared with those of male participants (n = 317) with MCI from the National Institutes of Health-funded Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. Between the two studies, those in the new analysis were slightly younger with a lower frequency of at least 1 APOE ε allele than those with MCI in the NIH-funded study. Additionally, they also had slightly lower MMSE scores, and higher hippocampal volumes compared with participants in ADNI.

"Beyond the presence of other pathologies, additional mechanisms may account for the discrepancies between our results and previous epidemiological studies. TBI and PTSD may also lead to cognitive decline/dementia via reduced cognitive reserve, non-Aβ/tau–mediated synaptic dysfunction, and/or neuroinflammation," the study investigators wrote. “Synaptic dysfunction is implicated as an early pathological event in AD and may be the final common biological mechanism most proximal to neurodegeneration that links protein pathologies to disease symptoms."

REFERENCE
1. Weiner MW, Harvey D, Landau SM, et al. Traumatic brain injury and post-traumatic stress disorder are not associated with Alzheimer’s disease pathology measured with biomarkers. Alzheimers Dement. Published online June 29, 2022. doi:10.1002/alz.12712