Brandon E Gavett, Robert A Stern, Robert C Cantu, Christopher J Nowinski and Ann C McKee*
Corresponding author: Ann C McKee firstname.lastname@example.org
Alzheimer's Research & Therapy 2010, 2:18 doi:10.1186/alzrt42
(2010-11-24 12:30) University of Pittsburgh
I agree with Dr. Gavett and colleagues that cohort studies with both detailed and
accurate neuropathological assesement of patients diagnosed with head injury are needed.
However, we also need more studies that would examine the mechanism of the association
between traumatic brain injury and Alzheimer��s disease.
Several population based studies favored an association between traumatic brain injury
and subsequent Alzheimer��s disease[1,2]. For instance, a hazard ratio of 2.32 (confidence
interval = 1.04 to 5.17) for moderate traumatic brain injury and a hazard ratio of
4.51 (confidence interval = 1.77 to 11.47) for severe head injury was observed in
a historical cohort study of 548 World War II veterans. We have reported that the
proportion of patients diagnosed with both traumatic brain injury and Alzheimer��s
disease was nearly twice as high as the proportion of patients diagnosed with Alzheimer��s
disease and any other comorbidities (p less than 0.001). In the adjusted (for age,
gender, length of stay and primary source of payment) logistic regression analysis,
patients diagnosed for traumatic brain injury were 1.82 times more likely to be diagnosed
with Alzheimer��s disease (95% confidence interval 1.28 �� 2.58). A recent meta-analysis
of case-control studies confirmed that men diagnosed with traumatic brain injury are
at increased risk of developing Alzheimer��s disease. However, no serious consideration
of the mechanism has been provided.
Obviously, trauma may damage any structure of the brain; however, cerebral vascular
wall could be at particular high risk due to the presence of ��internal�� forces acting
inside the vessel (i.e. shear stress). On the other hand, with the appearance of the
��hypoperfusion�� theory as well as findings from numerous population-based studies
linking Alzheimer��s disease to vascular disorders (i.e. hypertension, atherosclerosis
etc.), it became evident that the important task for understanding Alzheimer��s disease
is to thoroughly examine hemodynamics and blood rheology. Such approach may also result
in finding of successful treatments of Alzheimer��s disease.
Thus, the mechanism of the association between traumatic brain injury and Alzheimer��s
disease is complex. For instance, genetic influence (i.e. having apolipoprotein E
epsilon4) can worsen prognosis of Alzheimer��s disease after traumatic brain injury[6,7].
Animal-based experiments observed an increase of amyloid �� peptide following traumatic
brain injury. The vascular component of the mechanism of traumatic brain injury-related
Alzheimer��s disease should take into account both direct and indirect trauma to brain
vessels, and therefore changes to local hemodynamic and rheological factors. Traumatic
compression of the vessel can lead to the appearance of zones with high shear stress
(as the result of injury to part of the vessel) and low or zero shear stress (within
the zone of boundary layer separation). We have reported that high shear stress
(exceeding the physiological value) may potentially damage the endothelium and
increase platelet aggregation[10,11], possibly leading to thrombus formation. On the
other hand, trauma may lead to boundary layer separation, resulting in the appearance
of a zone with zero shear stress and zero yield velocity. According to current
research, this may result in an increase of blood viscosity through increased erythrocyte
aggregation and rouleaux formation. As noted above, hyperviscosity may worsen the
blood circulation and cause ischemia and local necrosis through deterioration in capillary
perfusion. Finally, trauma may lead to the appearance of zones of boundary layer
separation, which, in turn, may directly influence the velocity of the movement of
the regional brain extravascular fluid. The above consideration of regional brain
extravascular fluid dynamics is particularly important in light of the fact that certain
waste products such as glutamate or calcium can accumulate there causing degradation
of certain cellular components thus playing an important role in the pathogenesis
of Alzheimer��s disease[13,14].
Rovshan M Ismailov, M.D., M.P.H., Ph.D.
 Lye TC, Shores EA. Traumatic brain injury as a risk factor for Alzheimer's disease:
a review. Neuropsychol Rev 2000; 10(2):115-29.
 Jellinger KA. Head injury and dementia. Curr Opin Neurol 2004; 17(6):719-23.
 Plassman BL, Havlik RJ, Steffens DC et al. Documented head injury in early adulthood
and risk of Alzheimer's disease and other dementias. Neurology 2000; 55(8):1158-66.
 Ismailov RM. New insights into the mechanism of Alzheimer's disease: A multidisciplinary
approach . edn. Amazon Kindle, 2010.
 Fleminger S, Oliver DL, Lovestone S, Rabe-Hesketh S, Giora A. Head injury as
a risk factor for Alzheimer's disease: the evidence 10 years on; a partial replication.
J Neurol Neurosurg Psychiatry 2003; 74(7):857-62.
 Teasdale GM, Nicoll JA, Murray G, Fiddes M. Association of apolipoprotein E
polymorphism with outcome after head injury. Lancet 1997; 350(9084):1069-71.
 Chiang MF, Chang JG, Hu CJ. Association between apolipoprotein E genotype and
outcome of traumatic brain injury. Acta Neurochir (Wien) 2003; 145(8):649-53; discussion
 Blasko I, Beer R, Bigl M et al. Experimental traumatic brain injury in rats
stimulates the expression, production and activity of Alzheimer's disease beta-secretase
(BACE-1). J Neural Transm 2004; 111(4):523-36.
 Ismailov RM, Shevchuk NA, Schwerha J, Keller L, Khusanov H. Blunt trauma to
large vessels: a mathematical study. Biomed Eng Online 2004; 3(1):14.
 Jen CJ, McIntire LV. Characteristics of shear-induced aggregation in whole
blood. J Lab Clin Med 1984; 103(1):115-24.
 Wagner CT, Kroll MH, Chow TW, Hellums JD, Schafer AI. Epinephrine and shear
stress synergistically induce platelet aggregation via a mechanism that partially
bypasses VWF-GP IB interactions. Biorheology 1996; 33(3):209-29.
 Kwaan HC, Bongu A. The hyperviscosity syndromes. Semin Thromb Hemost 1999;
 Mattson MP. Calcium as sculptor and destroyer of neural circuitry. Exp Gerontol
 Khachaturian ZS. The role of calcium regulation in brain aging: reexamination
of a hypothesis. Aging (Milano) 1989; 1(1):17-34.
I declare that I have no significant competing interests
BioMed Central Ltd unless otherwise stated. Part of Springer Science+Business Media.