Cited by 594Dementia and Cognitive Impairment ResearchTraumatic Brain Injury ResearchAlzheimer's disease research and treatments

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Head Trauma as a Risk Factor for Alzheimer's Disease: A Collaborative Re-Analysis of Case-Control Studies

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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·1991·International Journal of Epidemiology

DOI 10.1093/ije/20.supplement_2.s28

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Abstract

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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“While still a somewhat controversial area, several studies recently have demonstrated a relationship between head injury and dementia (Mortimer et al., 1991; O'Meara et al., 1997; Salib & Hillier, 1997; Schofield et al., 1997); however, also see Mehta et al. (1999).”
The LEARn model: an epigenetic explanation for idiopathic neurobiological diseases
Lahiri, D. K., Maloney, B., & Zawia, N. H. (2009) · Molecular Psychiatry · doi:10.1038/mp.2009.82 · Cited by 212
Traumatic brain injury and young onset dementia: a nationwide cohort study
Nordström, P., Michaëlsson, K., Gustafson, Y., & Nordström, A. (2014) · Annals of Neurology · doi:10.1002/ana.24101 · Cited by 208
Epidemiology of late-life mental disorders
Hybels, C. F., & Blazer, D. G. (2003) · Clinics in Geriatric Medicine · doi:10.1016/s0749-0690(03)00042-9 · Cited by 210
“Head trauma has been found to be associated with later development of Alzheimer disease, although the results are not consistent [87,88].”
Result
The neuroinflammatory response in humans after traumatic brain injury
Smith, C., Gentleman, S. M., Leclercq, P. D., Murray, L. S., Griffin, W. S. T., Graham, D. I., & Nicoll, J. A. R. (2012) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12008 · Cited by 213
Head trauma preceding PD: A case-control study
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 205
Self-citation
Education and other socioeconomic determinants of dementia and Alzheimer's disease.
Mortimer, J. A., & Graves, A. B. (1993) · Cited by 214
Self-citation
NMDA 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 211
“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…”
Background
Morris water maze search strategy analysis in PDAPP mice before and after experimental traumatic brain injury
Brody, D. L., & Holtzman, D. M. (2005) · Experimental Neurology · doi:10.1016/j.expneurol.2005.10.020 · Cited by 196
“TBI is also the best-defined environmental risk factor for AD (Mortimer et al., 1991;Plassman et al., 2000;Thurman et al., 1999).”
Background
Chronic 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 202
Polypathology and dementia after brain trauma: Does brain injury trigger distinct neurodegenerative diseases, or should they be classified together as traumatic encephalopathy?
Washington, P. M., Villapol, S., & Burns, M. P. (2015) · Experimental Neurology · doi:10.1016/j.expneurol.2015.06.015 · Cited by 197
“The first analyzed 11 casecontrolled studies (Mortimer et al., 1991), the second analyzed 15 case-controlled studies (Fleminger et al., 2003).”
BackgroundResultInfluential
Sex and Gender Driven Modifiers of Alzheimer’s: The Role for Estrogenic Control Across Age, Race, Medical, and Lifestyle Risks
Rahman, 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 204
Untitled work
(2000) · doi:10.1002/1520-7560(2000)9999:9999
Risk for late-life re-injury, dementia and death among individuals with traumatic brain injury: a population-based study
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
“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
“…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).”
Amyloid β-peptide and amyloid pathology are central to the oxidative stress and inflammatory cascades under which Alzheimer's disease brain exists
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 176
“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 172
The role of apolipoprotein E in Alzheimer’s disease, acute brain injury and cerebrovascular disease: evidence of common mechanisms and utility of animal models
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
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
“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
ORCID: Fratiglioni, L
Jorm, A F
Rocca, W A
Shalat, S L
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
DOI: 10.1093/ije/20.supplement_2.s28
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 › Clinical Neurology › Traumatic Brain Injury Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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Head Trauma as a Risk Factor for Alzheimer's Disease: A Collaborative Re-Analysis of Case-Control Studies

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