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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: 03 September 2017 - Last content update released on 22 Sep 2017.

Risk Factor Overview

Cite as:

Koyama A, Weuve J, Mendez M*, Oppong A*, Rothman J*, Jackson JW, Blacker D. *contributed equally. "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; resul