Is head trauma a risk factor for Alzheimer disease?

Robert W. Griffith, MD
March 9, 2000 (Reviewed: November 8, 2002)

Introduction

Sometimes a negative report from a study is good news - in this case, it's heartening to learn that mild head trauma is not a major risk factor for dementia or Alzheimer disease in the elderly. Previous reports have suggested such a relationship, while other studies have been inconclusive. Now the well-known Rotterdam Study has yielded data that appear fairly irrefutable. However, an even more recent study, using documented head injury in US in military personnel, reaches contradictory conclusions. Can these be reconciled?

The Rotterdam Study

All persons 55 or older living in a suburb of the Dutch city in 1990-1993 were invited to participate in this study of age-related effects. Approximately 8,000 (78%) accepted, and 6,645 of these participants who were free of dementia at baseline were enrolled.¹

A history of head trauma with loss of consciousness was assessed at baseline by self-
reporting at interview. Follow-up assessment of incident dementia was done at an average of 2.1 years later.

Apolipoprotein E typing, looking for the apolipoprotein-e4 allele (APOE-e4), was done in over 4,000 of the participants, including 102 of those with head trauma and dementia at follow-up.

Women comprised 59% of the participants; the mean age was 69 years at baseline. Over the follow-up period 129 subjects developed dementia, 91 (71%) of whom had Alzheimer disease. In general, these people were more often women, older, and less well educated.

The relative risks in those with a history of head trauma, adjusted for gender, age, and
education level, were 1.0 for dementia (95% CI, 0.5-2.0) and 0.8 (95% CI, 0.4-1.9) for
Alzheimer disease. There were no significant effects on these relative risks of repeated
compared with single head traumas, recent (less than 10 years prior) compared with more than 10-year old traumas, or more than (versus less than) 15 minutes' duration of
unconsciousness.

The genetic analyses showed no interaction between the presence of the APOE-e4 allele and history of head trauma in increasing the risk of dementia or Alzheimer disease.

Comment

Military records were abstracted from 1996 to1997 to find all cases of previous closed head injury. Head injury was defined as moderate if unconsciousness or memory loss lasted between 30 minutes and 24 hours, and severe if the duration was longer than 24 hours. A total of 548 such subjects formed the head injury group, and they were compared with 1,228 subjects hospitalized for other causes. APOE-e4 typing was done in all subjects.

All participants were then evaluated for the occurrence of dementia and Alzheimer disease, and the results analyzed using proportional hazards modeling. Hazards ratios were calculated before and after adjustment for age, educational level, alcohol and excessive tobacco use.

Moderate head injury was found to be associated with an increased risk of Alzheimer disease - hazards ratio 2.32 (95% CI, 1.04-5.17) - and severe head injury with an even grater risk - hazards ratio 4.51 ((95%CI, 1.77-11.47). Results for mild head injury were inconclusive. There was a slight but non-significant trend for a stronger association between Alzheimer disease and head injury in those subjects with APOE-e4 alleles.

The large prospective population-based Rotterdam study provided fairly strong evidence that mild head trauma is not a major risk factor for dementia or Alzheimer disease. Moreover, they deny a role for the APOE-e4 allele in subjects with a history of head trauma with respect to the development of dementia or Alzheimer disease. The authors point out two limitations of the study - a relatively short duration of follow-up, and reliance on recall of head trauma in the past.

The US veterans study was well designed and analyzed, but suffered from the theoretical disadvantage of being retrospective, rather than prospective. On the other hand, the head injuries were very well documented. The results appear to contradict the findings of the Rotterdam study. It should be noted, however, that the US investigators also found no evidence of an association between mild head injury and Alzheimer disease.

The findings of these two studies can be reconciled, to a certain extent. Minor head injury (loss of consciousness of less than 30 minutes) appears to have no significant association with the development of Alzheimer disease in either study. Moderate to severe head injury is, on the other hand, probably associated with an increased risk of later development of Alzheimer disease (as shown by the increased hazards ratio with increased severity of the injury in the second study). There is no evidence from either study to show that the presence of the APOE-e4 allele increases the risk of head injury leading to Alzheimer disease. However, further studies will doubtless clarify these relationships.

Sources

• Head trauma and risk of dementia and Alzheimer's disease KM. Mehta, A. Ott, S. Kalmijn, The Rotterdam Study. Neurology, 1999, vol. 53, pp. 1959--1962



• Documented head injury in early adulthood and risk of Alzheimer's disease and other dementias BL. Plassman, RJ. Havlik, DC. Steffens,  et al., Neurology, 2000, vol. 55, pp. 1158--1166

Related Links
Syllabus: Risk Factors for Alzheimer Disease

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