WASHINGTON, DC—Although more than forty years have passed since British neurosurgeon McDonald Critchley described severe memory problems in a sample of boxers—presumably the result of repeated head trauma—the relationship between brain injury and Alzheimer's disease has proven difficult to unravel. For years, there was scant evidence that head injuries endured by nonboxers posed an increased risk for Alzheimer's disease; although epidemiologic studies linking the two conditions began appearing in the 1980s, negative studies continue to be published with enough frequency to ensure that the issue remains controversial. And while recent reports have revealed in some injured brains neuropathologic changes that bear a remarkable resemblance to Alzheimer's disease, the interpretation and implications of these findings remain uncertain.

Nonetheless, some researchers believe that decoding the Alzheimer's disease/brain injury connection will have implications far beyond the possibility of warding off dementia in head trauma patients. "It gives you insight into what may be the base mechanism for Alzheimer's disease," said Gareth W. Roberts, BSc, PhD, MBA, who coauthored several studies on the relationship between the two conditions before becoming Chief Executive Officer of the Cambridge, UK bioinformatics firm Proteom. "And once you have a feeling for what the core pathologic process is, you can ask, 'What kinds of things might stop that?' "

Other investigators envision similarly lofty applications. "I look upon head injury [research] as a paradigm for understanding environmental risk factors for neurodegenerative diseases in general," said John Q. Trojanowski, MD, PhD, Professor of Pathology and Laboratory Medicine at the University of Pennsylvania. For most patients, he noted, environmental factors are likely to far outweigh genetic influences in the etiology of neurodegenerative disease. "I think if we can 'crack' head trauma, it will open up ways of thinking about other environmental causes of these diseases."

WHAT HAPPENS AFTER BRAIN INJURY?

Recent studies have provided "very strong evidence that there is a connection between head trauma and at least some of the pathology of Alzheimer's disease," Dr. Trojanowski said. For example, in a report at the recent World Alzheimer Congress 2000, Steven T. DeKosky, MD, and colleagues at the University of Pittsburgh Medical Center reported findings from neocortical samples taken from brain injury patients one and three days after injury. The samples, which were obtained by surgical resection and compared with postmortem samples from neurologically normal controls, revealed increases in amyloid precursor protein (APP), apolipoproteins E and D, and ß-amyloid (Aß). Many of the Aß deposits "had morphologic characteristics of classic amyloid plaques in Alzheimer's disease," Dr. DeKosky and colleagues reported.

Several studies have found that Aß deposition occurs in a third of fatal head injury cases, even in children who survived only a few hours. The Aß is generally distributed throughout the brain; its presence does not correlate with cerebral contusions, increased intracranial pressure, or intracranial hematomas. Neurofibrillary tangles may also occur. The nature of pathology depends in part on injury severity—tangles do not seem to occur after mild trauma—but "I don't think there's much insight into how severe the injury has to be" to trigger Alzheimer's disease–like pathology, Dr. Trojanowski said.

These changes make sense, Dr. Roberts said, if one accepts the view that Alzheimer's disease is largely an inflammatory process. APP is found in synapses, he noted, and "one of the things we do know happens after brain injury is synaptic remodeling." Moreover, electron microscopy shows that synapses are involved in amyloid plaque formation. This may be a repair process of some sort, he said, but "instead of being shut down when it is appropriate, it just carries on. It becomes a bit like arthritis, where mechanisms that should help you instead become chronically activated and disabling."

It should be noted, however, that the neuropathology of brain injury is by no means a carbon copy of the changes that occur in Alzheimer's disease. For example, levels of growth inhibitory factor are increased in reactive astrocytes in experimentally induced brain injury, whereas these levels are reduced throughout the brain in Alzheimer's disease. Moreover, the neocortical distribution of neurofibrillary tangles is more superficial in former boxers with dementia pugilistica, or punch drunk syndrome, than in Alzheimer's disease patients.

HOW LARGE IS THE RISK?

Despite the array of pathologic evidence linking the disorders, the relationship between Alzheimer's disease and head injury remains unsettled from an epidemiologic standpoint. Findings reported last year from the Rotterdam Study, for example, found no increased risk of Alzheimer's disease in subjects with a history of head injury. Nonetheless, positive studies outnumber negative ones, and head injury is "becoming more accepted as being associated with the risk of Alzheimer's disease," said Brenda L. Plassman, PhD, Director of the Program in Epidemiology of Dementia at Duke University Medical Center, Durham, North Carolina.

In a new report that Dr. Trojanowski called "the most exhaustive and thoroughly done [epidemiologic] study I've seen," Dr. Plassman and colleagues performed telephone screening of more than 2,000 World War II veterans who had been hospitalized for head injury, pneumonia, or puncture wounds in 1944 or 1945. Subjects who screened positive for possible dementia underwent a three-hour exam that included neuropsychologic testing, neurologic examination, and DNA collection.

From 1940s armed forces hospital records, the researchers were able to estimate the severity of each subject's head injury, based on the occurrence of amnesia or skull fracture and the duration of unconsciousness. The findings revealed that "the more severe the injury, the greater the risk of Alzheimer's disease and dementia"; the relative risks (compared with controls) ranged from about 2 for moderate head injury to 4 for severe injury. The findings are consistent with those from most other positive epidemiologic studies, Dr. Plassman said. "It's rather striking that all of these studies used different samples, methods, and criteria for head injury, yet all have odds ratios that are pretty close." The relative risk of Alzheimer's disease after head injury is roughly similar to that reported for subjects heterozygous for the apolipoprotein E, (APOE)E4 allele, she added.

The study, which was reported, in part, at the February 1999 meeting of the International Neuropsychological Society, was published in the October 24 issue of Neurologywith an expanded sample size and the inclusion of new genetic data.

THE GENETIC CONNECTION

The role of genetic vulnerability is suggested by the fact that only a subset of brain injury patients develop amyloid pathology. Many investigators believe APOEgenotype is the key culprit. "There is a clear relationship between having an APOE*E4 allele and your likelihood of developing plaques after a head injury," Dr. Roberts said. "So in a sense the APOE/head injury story gives you the first genetic–environmental interaction in a neurologic disease." This relationship is consistent with APOE's proposed role in the maintenance and repair of neuronal membranes, synaptogenesis, and other processes. Indeed, researchers at the University of Glasgow reported earlier this year that the densities of the ß-amyloid peptides Aß-42 and Aß-40 in head injury patients were related in a dose-dependent manner to APOE*E4 endowment.

However, it is possible that in many cases head injury doesn't induce Alzheimer's disease–like pathology so much as accelerate its arrival. A 1989 retrospective study found that a history of head injury was associated with earlier onset of Alzheimer's disease. And last year, a report from the Mayo Clinic suggested that Alzheimer's disease rates were not elevated among subjects with a history of head trauma, but that the head injury hastened the time to Alzheimer's disease onset by about eight years.

FUTURE INTERVENTIONS

Can prompt, appropriate treatment after brain injury reduce or prevent the development of Alzheimer's disease–like pathology? While the mouse model for Alzheimer's disease that Dr. Trojanowski and others have been using has yielded interesting findings, the rodents' lack of tau pathology and "quirky" behavior did not allow for ideal testing of therapeutic interventions. However, recent work by Dr. Trojanowski and his colleagues, Tracy McIntosh, PhD, and Virginia Lee, PhD, may change that. "I think we may be moving closer to a meaningful model of how to understand the effects of head trauma on amyloid," he said.

At present, "aside from telling football players and soccer players to either not play or to wear a helmet, there's not much in the way of interventions," Dr. Trojanowski noted. However, as researchers gain a better understanding of the relationship between trauma, risk factors, and genetic vulnerability, medical advice could theoretically be targeted to a patient's profile: "If you're APOE*E4 homozygous, you should really think twice about playing football. If you're heterozygous for APOE*E4, you'd better wear a helmet and take vitamin E and aspirin for the rest of your life."

Moreover, the inflammatory model of Alzheimer's disease pathogenesis offers obvious potential for intervention. Epidemiologic studies have found a reduced rate of Alzheimer's disease among people who regularly used nonsteroidal anti–inflammatory drugs. And a study in the August 1 Journal of Neurosciencefound that ibuprofen reduced not only inflammation, but Aß plaque burden in a transgenic mouse model for Alzheimer's disease.

Nonetheless, crucial questions remain unanswered. "One of the things that needs fitting together is the link in the biology between the presenilins and APP. [We don't know] how they interact, what the normal function [of presenilins is], and the relationship between that function and the inflammatory process," Dr. Roberts said. Answering these questions, he noted, "would open up clear avenues for drug discovery."

NR