Traumatic brain injury as a risk factor for Alzheimer disease. Comparison of two retrospective autopsy cohorts with evaluation of ApoE genotype
Open accessAbstract
BACKGROUND AND PURPOSE: The impact of traumatic brain injury (TBI) on the pathogenesis of Alzheimer disease (AD) is still controversial. The aim of our retrospective autopsy study was to assess the impact of TBE and ApoE allele frequency on the development of AD. MATERIAL AND METHODS: We examined 1. the incidence of AD pathology (Braak stageing, CERAD, NIA-Reagan Institute criteria) in 58 consecutive patients (mean age +/- SD 77.0 +/- 6.8 years) with residual closed TBI lesions, and 2. the frequency of TBI residuals in 57 age-matched autopsy proven AD cases. In both series, ApoE was evaluated from archival paraffin-embedded brain material. RESULTS: 1. TBE series: 12.1 % showed definite and 10.3% probable AD (mean age 77.6 and 75.2 years), only 2/13 with ApoEepsilon3/4. From 45 (77.6%) non-AD cases (mean age 78.2 years), 3 had ApoEepsilon3/4. The prevalence of 22.4% AD in this small autopsy cohort was significantly higher than 3.3% in a recent large clinical series and 14% in the general population over age 70. 2. In the AD cohort with ApoEepsilon4 allele frequency of 30% similar to other AD series, residuals of closed TBI were seen in 4 brains (7%) (mean age +/- SD 78.2 +/- 6.4), all lacking the ApoEepsilon4 allele. TBI incidence was slightly lower than 8.5% in the clinical MIRAGE study. CONCLUSIONS: The results of this first retrospective autopsy study of TBI, ApoEepsilon allele frequency, and AD confirm clinical studies suggesting severe TBI to be a risk factor for the development AD higher in subjects lacking ApoEepsilon4 alleles. Further studies in larger autopsy series are needed to elucidate the relationship between TBI, genetic predisposition, and AD.
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Among individuals who have sustained TBI, those with lower testosterone levels appear to have an increased risk for Alzheimer's disease.
“Of the individuals who have sustained TBI, those with lower T levels also appear to have an increased risk for Alzheimer's disease, which makes the connection between sex hormones and brain injury even more intriguing (65).”
From Pituitary Dysfunction After Traumatic Brain Injury: A Clinical and Pathophysiological Approach (2015) · cites this paper as [65]
The Abstract Conclusions and Discussion report an association between TBI and Alzheimer disease. They do not address whether testosterone levels change that risk among people with TBI; searches for testosterone, lower T levels, and androgens found no such passage. No page numbers are available in our copy. (LLM, conf=0.85)
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“Fortythree of the publicationswere specific to the association of the APOE gene with outcomes after TBI [6,19–22, 24,25,28–30,32,41–72]; one was a meta-analysis [6].”
Traumatic Brain Injury-Induced Ependymal Ciliary Loss Decreases Cerebral Spinal Fluid Flow
Xiong, G., Elkind, J. A., Kundu, S., Smith, C. J., Antunes, M. B., Tamashiro, E., Kofonow, J. M., Mitala, C. M., Cole, J., Stein, S. C., et al. (2014) · Journal of Neurotrauma · doi:10.1089/neu.2013.3110 · Cited by 43 · see citing works
Clinical picture and the treatment of TBI-induced hypopituitarism
Caputo, M., Mele, C., Prodam, F., Marzullo, P., & Aimaretti, G. (2019) · Pituitary · doi:10.1007/s11102-019-00956-w · Cited by 39 · see citing works
Chang, P., Williams, A. M., Bhatti, U. F., Biesterveld, B. E., Liu, B., Nikolian, V. C., Dennahy, I. S., Lee, J., Li, Y., & Alam, H. B. (2019) · Journal of the American College of Surgeons · doi:10.1016/j.jamcollsurg.2018.12.026 · Cited by 36 · see citing works
Galveston Brain Injury Conference 2010: Clinical and Experimental Aspects of Blast Injury
Masel, B. E., Bell, R. S., Brossart, S., Grill, R. J., Hayes, R. L., Levin, H. S., Rasband, M. N., Ritzel, D. V., Wade, C. E., & DeWitt, D. S. (2012) · Journal of Neurotrauma · doi:10.1089/neu.2011.2258 · Cited by 36 · see citing works
“In addition to those related to sports injuries, numerous studies in civilian (Jellinger et al., 2001) and military (Plassman et al., 2000) populations have demonstrated a significant link between TBI and dementia.”
Jullienne, A., & Badaut, J. (2013) · Future Neurology · doi:10.2217/fnl.13.55 · Cited by 33 · see citing works
“However, it is well described that longterm risks of developing epilepsy and cognitive impairment are increased after stroke and TBI [20–22], as well as the increased risk of cognitive decline and development of Alzheim er’s disease following TBI [23].”
BackgroundChronic traumatic encephalopathy – neuropathology in athletes and war veterans
Lakis, N. S., Corona, R. J., Toshkezi, G., & Chin, L. S. (2013) · Neurological Research · doi:10.1179/1743132813y.0000000177 · Cited by 31 · see citing works
Concussion susceptibility is mediated by spreading depolarization-induced neurovascular dysfunction
Parker, E., Aboghazleh, R., Mumby, G., Veksler, R., Ofer, J., Newton, J., Smith, R., Kamintsky, L., Jones, C. M. A., O’Keeffe, E., et al. (2021) · Brain · doi:10.1093/brain/awab450 · Cited by 31 · see citing works
O'Hara, R. M., Luzon, A., Hubbard, J. T., & Zeitzer, J. M. (2009) · The Journal of Rehabilitation Research and Development · doi:10.1682/jrrd.2008.10.0140 · Cited by 31 · see citing works
“conducted the first retrospective autopsy study of TBI, APOE ε4 allele frequency, and AD, in which they also found that severe TBI was a risk factor for the development of AD, most particularly in non-APOE ε4 carriers [56–57].”
BackgroundTraumatic brain injury or traumatic brain disease: A scientific commentary
Obasa, A. A., Olopade, F. E., Juliano, S. L., & Olopade, J. O. (2024) · Brain Multiphysics · doi:10.1016/j.brain.2024.100092 · Cited by 29 · see citing works
Is zinc the link between compromises of brain perfusion (excitotoxicity) and Alzheimer's disease?
Frederickson, C. J., Cuajungco, M. P., & Frederickson, C. J. (2005) · Journal of Alzheimer s Disease · doi:10.3233/jad-2005-8208 · Cited by 28 · see citing works
“More evidence has recently confirmed this observation in humans and in the AD transgenic mouse model [27,37,40,41,51,57,65,72].”
A systematic review of large animal models of combined traumatic brain injury and hemorrhagic shock
Mayer, A. R., Dodd, A. B., Vermillion, M. S., Stephenson, D. D., Chaudry, I. H., Bragin, D. E., Gigliotti, A. P., Dodd, R. J., Wasserott, B. C., Shukla, P., et al. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.06.024 · Cited by 23 · see citing works
“, 1997), as well as a higher prevalence of pathological features characteristic of dementia upon autopsy (Jellinger et al., 2001).”
BackgroundRalston, B., Rable, J., Larson, T., Handmaker, H., & Lifshitz, J. (2019) · Journal of Aggression Maltreatment & Trauma · doi:10.1080/10926771.2019.1637988 · Cited by 23 · see citing works
Gibbons, L. E., Power, M. C., Walker, R. L., Kumar, R. G., Murphy, A., Latimer, C. S., Nolan, A., Melief, E. J., Beller, A., Bogdani, M., et al. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-221224 · Cited by 20 · see citing works
Regenerative Medicine and Traumatic Brain Injury: From Stem Cell to Cell-Free Therapeutic Strategies
Cui, L., Saeed, Y., Li, H., & Yang, J. (2021) · Regenerative Medicine · doi:10.2217/rme-2021-0069 · Cited by 19 · see citing works
Factores de riesgo de la enfermedad de Alzheimer
Quintana, J. L. B., Allam, M. F., del Castillo, A. S., & Navajas, R. F. (2005) · Revista de Neurología · doi:10.33588/rn.4010.2004360 · Cited by 18 · see citing works
Nihonmatsu-Kikuchi, N., Yu, X., Matsuda, Y., Ozawa, N., Ito, T., Satou, K., Kaname, T., Iwasaki, Y., Akagi, A., Yoshida, M., et al. (2021) · Communications Biology · doi:10.1038/s42003-021-02404-7 · Cited by 16 · see citing works
Chu, S.-F., Chiu, W.-T., Lin, H.-W., Chiang, Y., & Liou, T.-H. (2016) · Asia-Pacific journal of public health · doi:10.1177/1010539516662956 · Cited by 17 · see citing works
Gong, P., Xu, X., Shi, J., Ni, L., Huang, Q., Xia, L., Nie, D., Lu, X., Chen, J., & Shi, W. (2013) · PLoS ONE · doi:10.1371/journal.pone.0081747 · Cited by 13 · see citing works
“With further research, accumulating epidemiological evidence implicates traumatic brain injury (TBI) as a potential risk factor for AD or PD [3,4].”
BackgroundBrown, S. (2006) · Epilepsia · doi:10.1111/j.1528-1167.2006.00682.x · Cited by 11 · see citing works
“In some people a genetic predisposition may increase the risk of developing Alzheimer’s disease after brain injury (24).”
BackgroundModifiable dementia risk factors and AT(N) biomarkers: findings from the EPAD cohort
Roccati, E., Bindoff, A. D., Collins, J. M., Eastgate, J., Borchard, J., Alty, J., King, A. E., Vickers, J. C., Carboni, M., & Logan, C. A. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1346214 · Cited by 10 · see citing works
Santiago-Castañeda, C., Segovia‐Oropeza, M., Concha, L., Orozco-Suárez, S. A., & Rocha, L. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-200914 · Cited by 8 · see citing works
“It is known that TBI represents the most robust environmental risk factor for Alzheimer’s disease [20–22].”
Late-Onset Alzheimer's Disease: Risk Factors, Clinical Diagnosis and the Search for Biomarkers
Herrera-Rivero, M. (2013) · InTech eBooks · doi:10.5772/53775 · Cited by 7 · see citing works
“TBI has been associated with an increased risk to develop AD by longitudinal and retrospective studies, suggesting an effect between severity and repetitive episodes of TBI particularly by an increase in amyloid deposition [5, 6].”
BackgroundSignaling Pathways Involved in Cognitive Enhancement
Nelson, T. J., Sun, M., & Alkon, D. L. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-417042-1.00002-4 · Cited by 6 · see citing works
Blood–Brain Barrier Dysfunction and Exposure to Head Impacts in University Football Players
Jones, C. M. A., Kamintsky, L., Parker, E., Kureshi, N., Audas, L., Wilson, L., Champagne, A. A., Boulanger, M.-M., Distefano, V. J., Fenerty, L., et al. (2023) · Clinical Journal of Sport Medicine · doi:10.1097/jsm.0000000000001164 · Cited by 6 · see citing works
Amylin Pharmacology in Alzheimer’s Disease Pathogenesis and Treatment
Casadesus, G., Corrigan, R. R., & Piontkivska, H. (2021) · Current Neuropharmacology · doi:10.2174/1570159x19666211201093147 · Cited by 6 · see citing works
“These range from traumatic brain injury [14-18], viruses [19, 20] or toxins [21-24] to socioeconomic aspects such as low education levels [25], or lifestyle choices such as a sedentary lifestyle [26, 27].”
Traumatic Brain Injury Across the Lifespan: A Neuropsychological Tutorial for Attorneys
Richards, P. M., & Kirk, J. W. (2010) · Psychological Injury and Law · doi:10.1007/s12207-010-9065-0 · Cited by 5 · see citing works
“1996), headache (Packard 1999), substance abuse (Corrigan 2005), Alzheimer’s Disease (Jellinger et al. 2001), and other medical conditions.”
BackgroundWang, J., Zheng, B. L., Yang, S. J., Jian, F., Sun, H., & Wang, J. (2022) · Journal of Biomedical Nanotechnology · doi:10.1166/jbn.2022.3240 · Cited by 4 · see citing works
Neuro-proteomics and Neuro-systems Biology in the Quest of TBI Biomarker Discovery
Wang, K. K. W., Zhang, Z.-Q., & Kobeissy, F. (2014) · CRC Press eBooks · doi:10.1201/b17644-7 · Cited by 4 · see citing works
Blunt Traumatic Brain Injury and Alzheimer Pathology
Jellinger, K. A. (2022) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000527686 · Cited by 3 · see citing works
Self-citationMcLeod, R. E., Kale, K. M., Weglinski, C., Masoud, A. M., Akbar, N., Probert, F., Anthony, D. C., & Zainal, J. (2025) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2025.07.027 · Cited by 2 · see citing works
Gan, S., Sun, Y., Liu, K., Jia, X., Li, X., Zhang, M., & Bai, L. (2024) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.12550 · Cited by 2 · see citing works
“27,39 Given the vulnerability of the temporal lobes to mTBI, voxel-wise group comparisons of JD images were performed within the bilateral temporal lobes defined by the MNI structural atlas (Figure 2C).”
MethodPhenomenology of Coarse Brain Disease
Meller, W. H., Sheehan, W., & THURBER, S. D. (2008) · Humana Press eBooks · doi:10.1007/978-1-59745-252-6_26 · Cited by 2 · see citing works
Neuro-proteomics and Neuro-systems Biology in the Quest of TBI Biomarker Discovery
Alawieh, A. M., Sabra, Z., Zhang, Z., Kobeissy, F. H., & Wang, K. (2014) · CRC Press eBooks · doi:10.1201/b17644-3 · Cited by 2 · see citing works
Selmanovic, E., Gibbons, L. E., Folkerth, R. D., Keene, C. D., Nolan, A., Crane, P. K., Postupna, N. O., Lee, C. S., Latimer, C. S., Ariza, J., et al. (2026) · Journal of Alzheimer s Disease · doi:10.1177/13872877261457138 · Cited by 1 · see citing works
Effects of a Novel Stereoscopic Flow-Diverting Stent on Intracranial Aneurysm Hemodynamics
Zhao, Z., Qiu, H., Song, X., Xu, X., & Dong, Y. (2023) · Journal of Biomedical Nanotechnology · doi:10.1166/jbn.2023.3541 · Cited by 1 · see citing works
Traumatic Brain Injury and Neurodegenerative Disease
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Chlipala, M. L. (2010) · doi:10.12794/metadc30445
“In addition, individuals who have experienced a TBI have an increased risk for developing Alzheimer's disease (CDC, 2007, September 21; Friedman et al., 1999; Jellinger et al., 2001; Teasdale et al., 1997) as they age.”
Öst, M. (2015) · Gothenburg University Publications Electronic Archive (Gothenburg University)
THOSE WACKY, PUNCH-DRUNK KNUCKLEHEADS
Myronuk, L. D. S. (2003)
Walters, E. R. (2013) · Bradford Scholars (University of Bradford)
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- Authors
- Jellinger, K. A., Paulus, W., Wrocklage, C., & Litvan, I.
- Affiliations
- Ludwig Boltzmann für Klinische Neurobiologie (AT)
- University of Münster (DE)
- Henry M. Jackson Foundation (US)
- Corresponding author
- Jellinger, Kurt A
- Venue
- BMC Neurology
- Published
- 2001-07-30
- Volume
- 1
- Issue
- 1
- Pages
- 3-3
- ISSN
- 1471-2377 (ISSN-L)
- PMC
- PMC37390
- OpenAlex
- W1663695055
- Semantic Scholar
- 0b315ed8631bd947736544516e0673a6c2081db4
- Cited by
- 86
- References
- 34
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 5 · 2020: 2 · 2019: 7 · 2018: 2 · 2017: 2 · 2016: 4 · 2015: 9 · 2014: 8 · 2013: 7 · 2012: 4
- FWCI
- 0.40
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- BMC Neurology (publishedVersion)
- PubMed Central (publishedVersion, other-oa)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- traumatic brain injury, Alzheimer's disease, APOE ε4, APOE genotype, closed head injury, Braak staging, CERAD, genetic susceptibility
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Austria, Brain Injuries, Female, Gene Frequency, Genotype, Humans, Male, Retrospective Studies, Risk Factors, Cohort Studies, Comorbidity, Incidence, Prevalence, Apolipoprotein E3, Apolipoprotein E4
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