AlzRisk analyzes non-genetic risk factors for AD. For this reason, the AlzRisk team, which also includes director Deborah Blacker at Massachusetts General Hospital, Boston, and curator Alain Koyama at the University of California, San Francisco, included only those studies that looked at AD as an outcome, not those that measured cognitive decline or dementia of any type. They also favored studies with a prospective design, as those provide cleaner evidence for a connection than cross-sectional studies do, Weuve noted.

In the case of TBI, only four studies met inclusion criteria, and the data were mixed. A study of almost 2,000 World War II veterans found a twofold increased risk of AD in those who had suffered moderate or severe head trauma (see Plassman et al., 2000), while the smallest study showed a three- to fourfold higher risk of AD after brain injury (see Schofield et al., 1997). However, the two largest studies, European Studies of Dementia (see Launer et al., 1999) and Rotterdam (see Mehta et al., 1999), which were prospective, population-based studies with some overlap, saw no association between TBI and dementia. All four studies defined brain injuries as involving a loss of consciousness, and did not look at milder head trauma.

Weuve noted that in the future, the database may expand to include studies that analyze total dementia risk. In the case of TBI, these additional studies would strengthen the association with dementia (see AlzRisk discussion).

Some scientists draw a distinction between a single severe head injury and repeated mild concussions, noting that these different traumas may kick off separate disease pathways (see ARF related news story). Single, severe head injuries seem to trigger amyloid pathology in both humans and animals (see, e.g., Ikonomovic et al., 2004; Stone et al., 2002; and Chen et al., 2004). On the other hand, scientists believe that repeated mild TBIs cause a condition called chronic traumatic encephalopathy (CTE), which is characterized by tau and TDP-43 pathology instead of Aβ deposits (see ARF related news story and ARF Webinar). Military blast damage may fall into this category, too (see ARF related news story; ARF news story). Importantly, none of the studies included in the AlzRisk analysis looked at the effects of this type of brain injury.

Henrik Zetterberg at Sahlgrenska University Hospital in Mölndal, Sweden, wrote to Alzforum, “It is very interesting to learn that the new analyses in AlzRisk detect stronger associations between head injury and dementia in general, and only weak links to AD, specifically. These data resonate well, not only with our data, but also with data on chronic traumatic encephalopathy from Ann McKee and colleagues suggesting that repetitive head injury may cause a neuropathological cascade distinct from AD.”—Madolyn Bowman Rogers.