New AlzRisk Analysis: Brain Injury Promotes Dementia, But Is It AD?

Interest in the long-term effects of traumatic brain injury (TBI) has surged in recent years, fueled by reports of brain pathology in athletes and military personnel who suffer frequent concussions. Many animal studies also suggested a link between TBI and neurodegeneration. But does brain injury increase a person’s risk of getting Alzheimer’s disease? To answer this question, the curators of the AlzRisk database, hosted by Alzforum, recently completed a literature review and analysis of epidemiological studies in this area. Although only a handful of studies met the strict inclusion criteria, overall they pointed to a heightened risk of dementia after TBI, said project manager Jennifer Weuve at Rush University, Chicago, Illinois. What is not clear, however, is what kind of dementia. None of the studies included biomarker, imaging, or neuropathology data that could confirm the diagnosis of AD. More rigorous prospective studies that include neuropathology will be needed to answer this question, the AlzRisk analysis concludes.

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.

Comments

  1. The association of traumatic brain injury and Alzheimer's disease has been up for discussion for many years, and prompted us to perform biomarker studies on the topic. We analyzed CSF samples from boxers to test the hypothesis that this group of individuals, deliberately exposing themselves to very high doses of repetitive head trauma, would have biomarker evidence of Alzheimer's neuropathology. No such evidence was found; Aβ and p-tau levels were normal, i.e., no biomarker signs of plaque or tangle pathology.

    However, in two independent studies we saw acutely elevated CSF levels of cortical (total tau) and subcortical (neurofilament light, NFL) axonal injury markers in relation to the bout. The most pronounced changes were seen in boxers who had taken many hits to their heads and took many weeks to months to normalize. 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.

    References:

    Zetterberg H, Hietala MA, Jonsson M, Andreasen N, Styrud E, Karlsson I, Edman A, Popa C, Rasulzada A, Wahlund LO, Mehta PD, Rosengren L, Blennow K, Wallin A. Neurochemical aftermath of amateur boxing. Arch Neurol. 2006 Sep;63(9):1277-80. PubMed.

    Neselius S, Brisby H, Theodorsson A, Blennow K, Zetterberg H, Marcusson J. CSF-biomarkers in Olympic boxing: diagnosis and effects of repetitive head trauma. PLoS One. 2012;7(4):e33606. PubMed.

    Goldstein LE, Fisher AM, Tagge CA, Zhang XL, Velisek L, Sullivan JA, Upreti C, Kracht JM, Ericsson M, Wojnarowicz MW, Goletiani CJ, Maglakelidze GM, Casey N, Moncaster JA, Minaeva O, Moir RD, Nowinski CJ, Stern RA, Cantu RC, Geiling J, Blusztajn JK, Wolozin BL, Ikezu T, Stein TD, Budson AE, Kowall NW, Chargin D, Sharon A, Saman S, Hall GF, Moss WC, Cleveland RO, Tanzi RE, Stanton PK, McKee AC. Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model. Sci Transl Med. 2012 May 16;4(134):134ra60. PubMed.

    View all comments by Henrik Zetterberg

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References

News Citations

  1. Stress and Trauma: Aβ’s Mysterious Role in Severe Brain Injury
  2. Stress and Trauma: Shaken Brains, Shaken Lives
  3. Blast Anatomy—Chronic Traumatic Encephalopathy in Military Vets
  4. Stress and Trauma: Blast Injuries in the Military

Webinar Citations

  1. Sports Concussions, Dementia, and APOE Genotyping: What Can Scientists Tell the Public? What’s Up for Research?

Paper Citations

  1. Plassman BL, Havlik RJ, Steffens DC, Helms MJ, Newman TN, Drosdick D, Phillips C, Gau BA, Welsh-Bohmer KA, Burke JR, Guralnik JM, Breitner JC. Documented head injury in early adulthood and risk of Alzheimer's disease and other dementias. Neurology. 2000 Oct 24;55(8):1158-66. PubMed.
  2. Schofield PW, Tang M, Marder K, Bell K, Dooneief G, Chun M, Sano M, Stern Y, Mayeux R. Alzheimer's disease after remote head injury: an incidence study. J Neurol Neurosurg Psychiatry. 1997 Feb;62(2):119-24. PubMed.
  3. Launer LJ, Andersen K, Dewey ME, Letenneur L, Ott A, Amaducci LA, Brayne C, Copeland JR, Dartigues JF, Kragh-Sorensen P, Lobo A, Martinez-Lage JM, Stijnen T, Hofman A. Rates and risk factors for dementia and Alzheimer's disease: results from EURODEM pooled analyses. EURODEM Incidence Research Group and Work Groups. European Studies of Dementia. Neurology. 1999 Jan 1;52(1):78-84. PubMed.
  4. Mehta KM, Ott A, Kalmijn S, Slooter AJ, van Duijn CM, Hofman A, Breteler MM. Head trauma and risk of dementia and Alzheimer's disease: The Rotterdam Study. Neurology. 1999 Dec 10;53(9):1959-62. PubMed.
  5. Ikonomovic MD, Uryu K, Abrahamson EE, Ciallella JR, Trojanowski JQ, Lee VM, Clark RS, Marion DW, Wisniewski SR, Dekosky ST. Alzheimer's pathology in human temporal cortex surgically excised after severe brain injury. Exp Neurol. 2004 Nov;190(1):192-203. PubMed.
  6. Stone JR, Okonkwo DO, Singleton RH, Mutlu LK, Helm GA, Povlishock JT. Caspase-3-mediated cleavage of amyloid precursor protein and formation of amyloid Beta peptide in traumatic axonal injury. J Neurotrauma. 2002 May;19(5):601-14. PubMed.
  7. Chen XH, Siman R, Iwata A, Meaney DF, Trojanowski JQ, Smith DH. Long-term accumulation of amyloid-beta, beta-secretase, presenilin-1, and caspase-3 in damaged axons following brain trauma. Am J Pathol. 2004 Aug;165(2):357-71. PubMed.

External Citations

  1. AlzRisk database
  2. AlzRisk analysis
  3. AlzRisk discussion

Further Reading

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