Association of Traumatic Brain Injury With and Without Loss of Consciousness With Neuropathologic Outcomes in Community-Dwelling Older Persons

JAMA Netw Open. 2022 Apr 1;5(4):e229311. doi: 10.1001/jamanetworkopen.2022.9311.


Importance: A history of traumatic brain injury (TBI) has been considered a risk factor for Alzheimer dementia. However, the specific association of TBI, even without loss of consciousness (LOC), with pathologic findings that underlie Alzheimer dementia, including Alzheimer disease (AD), non-AD neurodegenerative, and vascular pathologic findings, remains unclear.

Objective: To examine the association between TBI with and without LOC and neuropathologic findings in community-based cohorts.

Design, setting, and participants: This cross-sectional analysis used neuropathologic data from 1689 participants from the Religious Orders Study, the Rush Memory and Aging Project, and the Minority Aging Research Study. These studies began enrollment in 1994, 1997, and 2004, respectively. The current study's data set was frozen on April 3, 2021, when the mean (SD) length of follow-up for the participants was 8.7 (5.5) years.

Exposure: Traumatic brain injury exposure was assessed using a standardized, self-reported questionnaire at baseline and annual follow-up visits. Participants were categorized into those (1) without TBI exposure (n = 1024), (2) with TBI with LOC (n = 161), or (3) with TBI without LOC (n = 504).

Main outcomes and measures: Neuropathologic measures of amyloid-β, paired helical filament tangles, neocortical Lewy bodies, transactive response DNA-binding protein 43, hippocampal sclerosis, gross infarcts, and microinfarcts were assessed. Multiple linear regression and logistic regression models were used to determine whether TBI with or without LOC (compared with no TBI exposure as the reference group) was associated with neuropathologic outcomes after adjusting for age at death, sex, and educational level. Whether the apolipoprotein E (APOE) ε4 allele and sex differences modified associations was also examined.

Results: A total of 1689 participants (1138 [67%] women and 551 [33%] men; mean [SD] age at death, 89.2 [6.7] years; 80 [5%] Black, 46 [3%] Latino, 1639 [97%] non-Latino, and 1601 [95%] White) participated in the study. Compared with participants without TBI, participants with TBI with LOC had a greater amyloid-β load (estimate, 0.25; 95% CI, 0.06-0.43; P = .008) and higher odds of having 1 or more gross infarcts (odds ratio [OR], 1.45; 95% CI, 1.04-2.02; P = .02) and 1 or more microinfarcts (OR, 1.70; 95% CI, 1.21-2.38; P = .002), particularly subcortical microinfarcts (OR, 1.85; 95% CI, 1.23-2.79; P = .002). Those with TBI without LOC had higher odds of neocortical Lewy bodies (OR, 1.37; 95% CI, 1.01-1.87; P = .04) and 1 or more cortical microinfarcts (OR, 1.43; 95% CI, 1.09-1.87; P = .008). The association of TBI with and without LOC with vascular pathologic outcomes persisted after controlling for vascular risk factors and vascular disease burden. Traumatic brain injury with or without LOC was not associated with paired helical filament tangles, transactive response DNA-binding protein 43, or hippocampal sclerosis. No interactions occurred with APOE ε4 or sex.

Conclusions and relevance: This cross-sectional analysis suggests that a history of TBI, even without LOC, is associated with age-related neuropathologic outcomes, both neurodegenerative and vascular. The variation in the neuropathologic outcomes in individuals with and without LOC may provide clues to potential mechanisms, diagnoses, and management in persons with TBI.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease* / complications
  • Amyloid beta-Peptides
  • Apolipoprotein E4
  • Brain Injuries, Traumatic* / complications
  • Brain Injuries, Traumatic* / epidemiology
  • Cross-Sectional Studies
  • DNA-Binding Proteins
  • Female
  • Humans
  • Independent Living
  • Infarction / complications
  • Male
  • Sclerosis / complications
  • Unconsciousness / epidemiology


  • Amyloid beta-Peptides
  • Apolipoprotein E4
  • DNA-Binding Proteins