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AlzRisk Risk Factor Discussion
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Risk Factor:
Risk Factor Type: Medical history
Current Understanding:
The evidence from observational epidemiologic studies provide some support for a harmful effect of head injuries, with risk especially elevated among those whose head injuries occur later in life or are more severe. However, few prospective studies have been conducted on head injury and AD, and they have significant methodological limitations. More importantly, the diagnosis of dementia in all prior studies has been based on clinical features rather than modern biomarker assays to identify the dementia subtype, and there have been no studies where the clinical diagnosis of AD was confirmed in pathologic studies. Thus, while head injury likely increases the risk of developing dementia, epidemiologic evidence linking head injury to AD dementia is less clear. There is much greater support for moderate to severe head injury in total dementia, and some support for mild head injury with loss of consciousness and total dementia. Of course, as there are many other harmful effects from head injury, there is ample support for current efforts to prevent head injuries. Moreover, the question of the impact of small recurrent injuries is under active investigation, and additional recommendations may emerge for youth, recreational, and professional sports and other activities in which these injuries are common. Prospective cohort studies are needed of individuals following TBI, with careful clinical evaluation and the addition of modern neuroimaging and biomarker tools and neuropathologic confirmation whenever possible. For a review of the putative mechanisms by which head injury may influence AD risk and detailed commentary on interpreting the findings below in a broader context, please view the Discussion.
Literature Extraction: Search strategy  * New *
Last Search Completed: 06 July 2011 - Last content update released on 17 Aug 2012.

Risk Factor Overview

Cite as:

Koyama A, Weuve J, Blacker D. "Head injury." The AlzRisk Database. Alzheimer Research Forum. Available at: http://www.alzrisk.org. Accessed [date of access]*.

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Introduction

The tables in the Risk Factor Overview present studies investigating the association between past history of head injury and risk of Alzheimer’s disease (AD) and total dementia (TD). As of yet, comparable results are available from too few independent populations for meta-analysis. Overall, however, these studies provide some support for a harmful effect of head injuries, with risk especially elevated among those whose head injuries occur later in life or are more severe. However, few prospective studies have been conducted on head injury and AD, and they have significant methodological limitations. More importantly, the diagnosis of dementia in all prior studies has been based on clinical features rather than modern biomarker assays to identify the dementia subtype, and there have been no studies where the clinical diagnosis of AD was confirmed in pathologic studies. Thus, while head injury likely increases the risk of developing dementia, epidemiologic evidence linking head injury to AD dementia is less clear.

Potential Mechanism of Action

Head injury can contribute to neurodegeneration through several possible pathways, including direct neuronal injury, damage to the blood-brain barrier, an elevated inflammatory state following trauma [1-3], and possibly other as yet unknown mechanisms. In a PET imaging study, microglial activation was seen in patients with traumatic brain injury (TBI) up to 17 years from the time of injury; increased microglial activation was present in both cortical and subcortical areas that were distant from the original site of injury [2]. Limited pathologic observations in humans who have survived for months and years after TBI also support the conclusion that microglial activation persists for a prolonged period [4]. Animal studies of head trauma also show systemic microglial activation, neuronal abnormalities, axonal injuries, and increased levels of reactive oxygen species [5, 6].

Head injury may also contribute specifically to AD neuropathology, although evidence is more limited and less consistent than that for nonspecific injury. In rodent models, TBI results in neurodegeneration and progressive brain atrophy that continues at least one year after injury [7, 8]. Several proteins associated with neurodegenerative disease in humans have been demonstrated to accumulate following experimental TBI in rodents. Notable among these are: amyloid precursor protein (APP), the precursor to brain amyloid and thus amyloid plaques, which is up-regulated immediately after TBI [9]; and its breakdown product amyloid-β peptide, which accumulates over weeks and months[9-11]. In triple transgenic mouse models, TBI results in accumulations of key proteins associated with AD neuropathology that persist up to one week after injury, and these mechanisms have been hypothesized to contribute to the long-term neurodegenerative effects of TBI [12].

Human pathologic studies addressing the mechanisms of post-TBI neurodegeneration are limited. Diffuse amyloid plaques are found in up to 30% of patients who die acutely following TBI [13]. Amyloid-β accumulation is rapid, and can be detected in tissue excised surgically within hours of injury [14, 15]. In a recent autopsy study of 39 individuals who survived between 1 and 47 years after a single TBI [16], amyloid plaques and neurofibrillary tangles were present in up to a third.

Tau inclusions creating neurofibrillary tangle-like lesions have also been associated with both classical dementia pugilistica, the dementia that occurs in boxers and others who have had repeated trauma to the head, as well as in recent examples of professional football players who develop a similar syndrome [17, 18]; still uncertain is the effect of blast injuries and concussive injuries that occur in warfare.

Whether these lesions represent a common final expression of differential pathobiological processes or share substantial overlap with the pathological cascade that leads to AD is a matter of conjecture, but in either case it is quite evident that traumatic brain damage, concussions, and other head injuries can certainly contribute to reduced cognitive reserve, and worsen the symptoms of AD.

Methodological Issues

Exposure

The reviewed studies varied in how they assessed, defined and further classified head injury. Each of the approaches has inherent advantages and disadvantages in capturing features of the head injury and injury-related pathology that are relevant to AD risk.

Head injury definition. The majority of studies adopted a broad definition of head injury, and all studies’ definitions included associated loss of consciousness (LOC). In contrast, one study used a narrower definition and considered only head injuries that were sustained during military service; resulted in LOC, amnesia, or skull fracture; did not penetrate the dura mater; and in which any acute cognitive impairment resolved within three months after injury [19]. As the definition of head injury becomes more restrictive, the likelihood increases that relevant injuries are missed. In particular, recurrent small injuries have been the focus of recent attention, although no studies involving such injuries met AlzRisk’s inclusion criteria. Conversely, broader definitions of head injury may include many less meaningful injuries.

Dimensions of head injury: severity and timing. The studies reviewed used similar criteria to classify head injuries, excluding less severe injuries without LOC, and generally including the most severe injuries. Therefore, the results of these studies are fairly comparable, and none offers much information about any effect of milder head injuries on AD risk. Some studies also investigated head injuries by timing (years prior to assessment) and severity (based on the duration of LOC), and total number of injuries. Overall, the results from these subanalyses suggest that head injuries characterized by an increased duration of LOC are associated with increased risk of AD. Some of the studies reviewed also examined the effect of head injuries based on when they occurred in the participants' lives, and did not find evidence of a difference in AD risk. However, data were only available from a small number of studies, and these findings may change as new studies become available.

Head injury assessment. Most of the studies reviewed relied on participant recall rather than medical records to assess the participant's history of head injury, making exposure assessment subject to recall bias. Although all participants were classified as cognitively normal at baseline, it is possible that subjects with undetected mild degrees of cognitive loss were less likely than those without such mild deficits to recall their head injuries, which would bias the results away from a deleterious association between head injury and AD risk. In addition, across all participants there might be underreporting of head injury, particularly less severe injuries [20, 21], or those that went unrecognized [22, 23], which would tend to attenuate any association. However, the studies we included only considered injuries that resulted in loss of consciousness, making underreporting less likely. Last, there might also be underreporting due to amnesia at the time of the injury itself, which would again attenuate the association.


Design and Analysis

Cohort selection. Among studies that met our inclusion criteria, two of the studies had populations that overlapped somewhat. One study was a pooled analysis of four European cohorts [24], one of which was the cohort used in another study [25]. Including results from overlapping populations may over-emphasize results from this particular cohort, which were in fact largely null. In addition, the studies reported here may have limited generalizability because a substantial fraction of them focus on military veterans, individuals who have unique exposures and differ to some extent demographically from the general population.

Bias due to dementia assessment. The necessarily limited assessment used in the epidemiologic diagnosis of the AD—with limited history, and little or no access to biomarkers, neuroimaging, or autopsy—poses particular concerns for evaluating the relationship between head injury and AD. First, classification of AD diagnosis may occur because the clinical presentation appears grossly similar to AD, but underlying pathology has not been assessed. If TBI leads to some other form of dementia, this misclassification may occur more frequently in those exposed to TBI, and thus overestimate the association with AD.

Second, misclassification may occur because the temporal relationship between head injury and the onset of AD may be unknown. While this issue is addressed to some extent by the prospective design of the studies reported here, epidemiological studies are limited in their clinical assessments. In clinical settings, there is careful effort to distinguish emergent from residual cognitive loss based on the timing, extent, and nature of the symptoms, but this distinction is much more difficult in epidemiologic settings. Moreover, mild degrees of cognitive impairment could have preceded the head injury, and could even have contributed to risk of head injury (e.g., from accidents).

Third, the studies we reviewed did not record multiple small head injuries, which may result in cognitive changes. This condition, sometimes referred to as chronic traumatic encephalopathy (CTE), shares some features with AD, although differs in its pathology. In CTE, extensive neurofibrillary tangles are found in different regions of the brain, while there is typically limited amyloid deposition. These distinctions are definitive only upon autopsy, which was not available in these studies.

Confounding and Effect Modification. Although each study adjusted its analyses for common sources of confounding, including age, sex, and education, other factors could confound an association between head injuries and AD risk. For example, alcohol use or stroke can lead to head injury, but also have independent effects on the risk of AD and cognitive impairment. Additionally, in studies with long follow-up periods, unmeasured or unadjusted factors that confer a survival advantage or disadvantage can lead to differential loss to follow up. Analyses not adjusting for these variables can result in biased estimates of the effect of head injuries on AD risk.

It is possible that carriers of the APOE ε4 allele are more susceptible to the influence of head injury on risk of AD. Although the reviewed studies showed minimal evidence suggesting such an interaction, prospective studies have reported a significant increased risk of total dementia after head injury only in carriers of the APOE ε4 allele [26, 27]. Additionally, post-mortem evidence suggests that such an association may be due to the acceleration of amyloid-beta deposition in APOE ε4 carriers following head injury [28].

Results from Other Lines of Research

Results from studies that examined the association between head injury and total dementia generally provide more robust support for a harmful effect of head injury. Most of these studies included population-based cohorts in North America or Europe [26, 27, 29-32], and one studied Aboriginal Australians [33]. Several of these studies reported a significant harmful effect of head injuries on TD risk, two reported a harmful effect only in participants with an APOE ε4 allele, and one was null.

A few studies have examined the impact of head injury on cognitive test performance in a diverse set of cohorts. In two retrospective cohort studies, one studying retired National Football League players and the other Vietnam veterans (with predominantly penetrating head injuries), those with head injuries in young adulthood performed worse than those without such injuries on neuropsychological tests administered decades later [34, 35]. In contrast, a small prospective cohort study showed that older patients with mild to moderate TBI did not differ in performance on neuropsychological tests from those who did not suffer TBI two years following injury [36].

The studies meeting the AlzRisk inclusion criteria generally elected to define head injuries as those involving at least some loss of consciousness (LOC). Recent work has suggested that recurrent mild head injuries without LOC may contribute to cognitive losses. Many of these studies report significant associations between a broader range of head injuries and an increased risk of TD [32, 35, 37].

Discussion and Recommendations

Overall, the studies reviewed provide only minimal support for a role of head injury in increasing future risk of AD dementia specifically. However, there is much greater support for moderate to severe TBI in total dementia, and some support for mild head injury with loss of consciousness and total dementia [38]. In addition, of course, as there are many other harmful effects from head injury, there is ample support for current efforts for head injury prevention. Moreover, the question of the impact of small recurrent injuries is under active investigation, and additional recommendations may emerge for youth, recreational, and professional sports and other activities in which these injuries are common. Finally, there is a need for prospective cohort studies of individuals following TBI, with careful clinical evaluation and the addition of modern neuroimaging and biomarker tools and neuropathologic confirmation whenever possible.


References

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