Head Trauma as a Risk Factor for Alzheimer's Disease: A Collaborative Re-Analysis of Case-Control Studies
Open accessAbstract
A re-analysis of the data from 11 case-control studies was performed to investigate the association between head trauma and Alzheimer's disease (AD). To increase comparability of studies, exposures were limited to head trauma with loss of consciousness (hereafter referred to as 'head trauma') and comparisons were restricted to community (versus hospital) controls. Test for heterogeneity across studies was negative; consequently, data were pooled in subsequent analyses. The pooled relative risk for head trauma was 1.82 (95% confidence interval: 1.26-2.67). Stratified analyses showed stronger associations in cases without a positive family history of dementia and in males (versus females). Adjustment of the pooled relative risk for family history of dementia, education and alcohol consumption did not alter significantly the association between head trauma and AD. There was no interaction effect between head trauma and family history of dementia, suggesting that these risk factors operate independently. Mean age of onset was not significantly different in cases with a history of head trauma compared to cases without such a history. The findings of the pooled analysis support an association between reported head trauma and AD.
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Repeated mTBI is a major risk factor for neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, fronto-temporal dementia, and chronic traumatic encephalopathy.
“In particular, repeated mTBI (rmTBI) has been identified as a major risk factor for neurodegenerative diseases including Alzheimer’s disease (AD) [100], Parkinson’s disease (PD) [68] amyotrophic lateral sclerosis (ALS) [21, 2], fronto-temporal dementia (FTD) [126, 124], and chronic traumatic encephalopathy (CTE) [95].”
From Early onset senescence and cognitive impairment in a murine model of repeated mTBI (2021) · cites this paper as [100]
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ResultThe neuroinflammatory response in humans after traumatic brain injury
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Bower, J. H., Maraganore, D. M., Peterson, B. J., McDonnell, S. K., Ahlskog, J. E., & Rocca, W. A. (2003) · Neurology · doi:10.1212/01.wnl.0000068008.78394.2c · Cited by 206 · see citing works
Self-citationEducation and other socioeconomic determinants of dementia and Alzheimer's disease.
Mortimer, J. A., & Graves, A. B. (1993) · Cited by 205 · see citing works
Self-citationNMDA Receptor Activation Inhibits α-Secretase and Promotes Neuronal Amyloid-β Production
Lesné, S., Ali, C., Gabriel, C., Croci, N., MacKenzie, E. T., Glabe, C. G., Plotkine, M., Marchand‐Leroux, C., Vivien, D., & Buisson, A. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.0849-05.2005 · Cited by 198 · see citing works
“Traumatic brain injuries (TBIs) have been identified as an environmental risk factor for Alzheimer’s disease (AD) (Heyman et al., 1984; Mortimer et al., 1991; Guo et al., 2000; Plassman et al., 2000; Uryu et al., 2002; Fleminger et al., 2003), an age-related neurodegenerative disease associated…”
BackgroundBrody, D. L., & Holtzman, D. M. (2005) · Experimental Neurology · doi:10.1016/j.expneurol.2005.10.020 · Cited by 195 · see citing works
“TBI is also the best-defined environmental risk factor for AD (Mortimer et al., 1991;Plassman et al., 2000;Thurman et al., 1999).”
BackgroundChronic Traumatic Encephalopathy: The Neuropathological Legacy of Traumatic Brain Injury
Hay, J. R., Johnson, V. E., Smith, D. H., & Stewart, W. B., Jr. (2016) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-012615-044116 · Cited by 193 · see citing works
Washington, P. M., Villapol, S., & Burns, M. P. (2015) · Experimental Neurology · doi:10.1016/j.expneurol.2015.06.015 · Cited by 190 · see citing works
“The first analyzed 11 casecontrolled studies (Mortimer et al., 1991), the second analyzed 15 case-controlled studies (Fleminger et al., 2003).”
BackgroundResultInfluentialRahman, A., Jackson, H. C., Hristov, H., Isaacson, R., Saif, N., Shetty, T., Etingin, O. R., Henchcliffe, C., Brinton, R. D., & Mosconi, L. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00315 · Cited by 190 · see citing works
Dams-O’Connor, K., Gibbons, L. E., Bowen, J. D., McCurry, S. M., Larson, E. B., & Crane, P. K. (2012) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2012-303938 · Cited by 178 · see citing works
“1–2 450 (13) 80 (14) 7 (11) 4 (13) 541 (13)”
Prolonged Activation of NF-κB Following Traumatic Brain Injury in Rats
NONAKA, M., CHEN, X.-H., PIERCE, J. E. S., LEONI, M. J., McINTOSH, T. K., WOLF, J. A., & SMITH, D. H. (1999) · Journal of Neurotrauma · doi:10.1089/neu.1999.16.1023 · Cited by 176 · see citing works
“…the potential of brain trauma to initiate or facilitate active neurodegenerative cascades, such as increasing the risk for the development of Alzheimer's disease (Mortimer et al., 1991) and inducing Alzheimer's disease-like pathologic changes shortly following injury (Roberts et al., 1991, 1994).”
Butterfield, D. A., Griffin, S. T., Münch, G. W., & Pasinetti, G. M. (2002) · Journal of Alzheimer s Disease · doi:10.3233/jad-2002-4309 · Cited by 174 · see citing works
“These are also overexpressed in fetuses, neonates, infants, children, and adults with Down’s syndrome (a condition where the entire array of Alzheimer-type changes accumulates gradually over the course of a few decades) and in head injury (known to increase risk for later development of Alzheimer’s disease [53]).”
Alzheimer's disease as a disorder of mechanisms underlying structural brain self-organization
Arendt, T. (2001) · Neuroscience · doi:10.1016/s0306-4522(00)00516-9 · Cited by 168 · see citing works
Horsburgh, K. J., McCarron, M. O., White, F., & Nicoll, J. A. R. (2000) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00097-x · Cited by 169 · see citing works
Gene-environment interactions in Alzheimer's disease: A potential path to precision medicine
Eid, A., Mhatre, I., & Richardson, J. R. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.03.005 · Cited by 164 · see citing works
“However, most earlier epidemiological studies support a role for TBI history in increasing risk of AD (Guo et al., 2000; Mortimer et al., 1991; Nicoll, Roberts, & Graham, 1995, 1996; Plassman et al., 2000; Schofield et al., 1997) and in some cases have associated a history of TBI with AD pathology (Jellinger, Paulus,…”
Result
- Authors
- Mortimer, J. A., Van Duijn, C. M., Chandra, V, Fratiglioni, L., Graves, A. B., Heyman, A., Jorm, A. F., Kokmen, E., Kondo, K., Rocca, W. A., Shalat, S. L., Soininen, H., & A Hofman for the Eurodem Risk Factors Research Group
- Affiliations
- Minneapolis VA Medical Center (US)
- Erasmus University Rotterdam (NL)
- Corresponding author
- Mortimer, J A
- Venue
- International Journal of Epidemiology
- Publisher
- Oxford University Press (OUP)
- Published
- 1991-01-01
- Volume
- 20
- Issue
- Supplement 2
- Pages
- S28-S35
- ISSN
- 0300-5771 (ISSN-L)
- 1464-3685
- OpenAlex
- W2142046013
- Cited by
- 594
- References
- 0
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 10 · 2023: 16 · 2022: 28 · 2021: 23 · 2020: 21 · 2019: 35 · 2018: 16 · 2017: 28 · 2016: 37 · 2015: 31 · 2014: 22 · 2013: 11 · 2012: 21
- FWCI
- 12.29
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- other-oa
- Locations
- International Journal of Epidemiology (publishedVersion)
- PubMed (publishedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- head trauma, Alzheimer's disease, risk factors, loss of consciousness, family history of dementia, sex differences, age of onset, pooled relative risk, case-control study
- MeSH terms
- Alzheimer Disease, Australia, Europe, Female, Craniocerebral Trauma, Humans, Male, Risk, Risk Factors, United States, Meta-Analysis as Topic, Case-Control Studies
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