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Herpes simplex virus and risk of Alzheimer's disease
THE LANCET
which were not represented sufficiently in the PHS to allow for detectable penetrance of the PlA2 risk. Similar observations have been made for other inherited risk factors, such as the factor V Leiden (FVL) risk for deep vein thrombosis (DVT). The risk for DVT associated with the FVL mutation in individuals who are concurrently antithrombin III deficient is 66 times the risk for DVT associated with FVL for individuals involved in the PHS. Thus, a restricted population was represented in the PHS report, and we note that Newman in his commentary accompanying Ridker’s report gave little consideration to the differences between the studies. He suggests burial for the PlA2 risk factor hypothesis. This critique was based, in part, on our finding that PlA2 platelets in plasma bind less exogenous fibrinogen than do PlA1 platelets.5 The importance of this finding remains: a functional difference between PlA1 and PlA2 platelets was identified, which supports the possibility that PlA2 is a risk factor for acute CHD. We appreciate that prospective studies are generally viewed more favourably than case-control analyses. However, the PHS consists of older male physicians with few risk factors, and generalisation to the population as a whole should be made cautiously, as repeatedly indicated by Ridker and co-investigators. A strict interpretation of their study would be that for older men with established risk factors, PlA2 positivity is not associated with acute CHD, a conclusion consistent with our data. Because the PHS report leaves unaddressed this possibility in younger populations and in women, it would be unfair to such individuals and their families to prematurely nail the coffin on an observation of potential benefit until additional scientific evidence is obtained and critically evaluated. *Paul F Bray, Ethan J Weiss, Matthew Tayback, Pascal J Goldschmidt-Clermont *Division of Haematology, Depar tment of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; and Ohio State University, Columbus, Ohio
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Ridker PM, Hennekens CH, Schmitz C, Stampfer MJ, Lindpainter K. PlA1/A2 polymorphism of platelet glycoprotein IIIa and risks of myocardial infarction, stroke, and venous thrombosis. Lancet 1997; 349: 385–88. Weiss EJ, Bray PF, Tayback MT, et al. The platelet glycoprotein IIIa polymorphism PlA2: an inherited platelet risk factor for coronary thrombotic events. N Engl J Med 1996; 334: 1090–94. Carter AM, Ossei-Gerning N, Grant PJ. Platelet glycoprotein IIIa PlA polymorphism in young men with myocardial infarction. Lancet 1996; 348: 485–86. Marenberg ME, Risch N, Berkman LF, Floderus B, de Faire U. Genetic
Vol 349 • April 12, 1997
5
susceptibility to death from coronary heart disease in a study of twins. N Engl J Med 1994; 330: 1041–46. Goldschmidt-Clermont PJ, Weiss EJ, Shear WS, et al. Platelets from PlA2(–) individuals bind more exogenous fibrinogen than platelets from PlA2(+) individuals. Blood 1996; 88: 26a.
colleagues are correct in postulating an association between HSV1 and AD. David S Latchman Windeyer Institute of Medical Sciences, Depar tment of Molecular Pathology, University College London Medical School, London W1P 6DB, UK
1
Herpes simplex virus and risk of Alzheimer’s disease SIR—Itzhaki and colleagues (Jan 25, p 241) report that the combination of herpes simplex virus type 1 (HSV1) in the brain and carriage of the apolipoprotein E ε4 (APOE-ε4) allele is a significant risk factor for Alzheimer’s disease (AD). This finding is provocative and will, hopefully, inspire further work, particularly since the investigators include only four nonAD individuals who had the APOE-ε4 allele. It is possible, therefore, that their findings are simply dependent on the APOE-ε4 allele being a significant risk factor for AD combined with the high frequency of HSV1 in the brains of elderly individuals with or without AD. Thus, the very high frequency of the APOE-ε4 allele in the patients with AD, together with the occurrence of HSV1 in all patients, would result in a high frequency of AD patients who were positive for APOE-ε4 and HSV1. Further studies that include a larger number of healthy individuals (controls) who carry the APOE-ε4 allele are needed to investigate whether such individuals show a much lower frequency of HSV1 infection than do carriers of APOE-ε4 who have AD. Nonetheless, the report by Itzhaki does provide the first tentative evidence of a link between HSV1 and AD. It is unfortunate, therefore, that the researchers chose to conclude the paper with the suggestion that their findings “call into question the proposed use of HSV1 as a vector for gene therapy”. This is clearly not the case. HSV1 is a human pathogen that produces cold sores in a wide range of individuals and a lethal encephalitis in a small number of people. Similarly, direct injection of HSV into the brain of animals produces severe encephalitis and death even at low doses of virus.2 All the laboratories involved in the development of HSVbased vectors for gene therapy are producing highly disabled viruses that contain several mutations that would prevent the replication or expression of virus gene products when introduced into animals or patients in gene therapy procedures.3,4 Given the highly disabled nature of these viruses, which is necessary to prevent the risk of cold sores or encephalitis, the risk that the viruses would produce AD is infinitesimally small, even if Itzhaki and
2
3
4
Itzhaki RF, Lin W-R, Shang D, et al. Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet 1997; 349: 241–44. Maclean AR, Fareed MU, Robertson L, Harland J, Brown SM. Herpes simplex virus type 1 deletion variants 1714 and 1716 pinpoint sequences involved in neurovirulence. J Gen Virol 1991; 72: 631–39. Coffin RS, Latchman DS. Herpes simplex virus based vectors. In: Latchman DS, ed. Genetic manipulation of the nervous system. London: DS Academic Press, 1995: 99–114. Fink DJ, DeLuca NA, Goins WF, Glorioso JC. Gene transfer to neurons using herpes simplex virus-based vectors. Ann Rev Neuroscience 1996; 19: 265–87.
Authors’ reply SIR—We agree that the number of healthy individuals with an APOE-ε4 allele is small. Unfortunately, it will be difficult to obtain specimens from a larger number of such individuals because the percentage of healthy people, especially of very elderly individuals, with this allele is low, and few normal brains are available in brain banks in the UK or USA. Furthermore, Latchman’s suggestion that APOE-ε4 on its own but not HSV1 is a risk factor is questionable. In the group that included 22% (10/46) of the AD patients who were HSV1-negative in brain, only one fifth possessed an APOE-ε4 allele, which argues against the latter alone being a significant risk; presumably, other unknown factors account for the disease in this group of patients. We analysed the hypothesis of simple multiplicative effects, but this was rejected in favour of the alternative: a synergistic effect. In addition, the highly significant difference between the allele frequencies of individuals who have cold sores and those who do not lends support to our proposal that the combination of HSV1 in brain and possession of an APOE-ε4 allele is damaging in the nervous system. Incidentally, we would like to emphasise a point about prevalence that was not made explicit in our report: the combination of HSV1 in brain and possession of an APOE-ε4 allele was found in 29 (63%) of the 46 patients with AD, compared with only two (5%) of the 44 healthy controls. Finally, our comment at the end of the report was merely a suggestion that caution should be exercised because of the possibility, even if very remote, that recombination between the resident latent HSV1 genome and the disabled
1101
which were not represented sufficiently in the PHS to allow for detectable penetrance of the PlA2 risk. Similar observations have been made for other inherited risk factors, such as the factor V Leiden (FVL) risk for deep vein thrombosis (DVT). The risk for DVT associated with the FVL mutation in individuals who are concurrently antithrombin III deficient is 66 times the risk for DVT associated with FVL for individuals involved in the PHS. Thus, a restricted population was represented in the PHS report, and we note that Newman in his commentary accompanying Ridker’s report gave little consideration to the differences between the studies. He suggests burial for the PlA2 risk factor hypothesis. This critique was based, in part, on our finding that PlA2 platelets in plasma bind less exogenous fibrinogen than do PlA1 platelets.5 The importance of this finding remains: a functional difference between PlA1 and PlA2 platelets was identified, which supports the possibility that PlA2 is a risk factor for acute CHD. We appreciate that prospective studies are generally viewed more favourably than case-control analyses. However, the PHS consists of older male physicians with few risk factors, and generalisation to the population as a whole should be made cautiously, as repeatedly indicated by Ridker and co-investigators. A strict interpretation of their study would be that for older men with established risk factors, PlA2 positivity is not associated with acute CHD, a conclusion consistent with our data. Because the PHS report leaves unaddressed this possibility in younger populations and in women, it would be unfair to such individuals and their families to prematurely nail the coffin on an observation of potential benefit until additional scientific evidence is obtained and critically evaluated. *Paul F Bray, Ethan J Weiss, Matthew Tayback, Pascal J Goldschmidt-Clermont *Division of Haematology, Depar tment of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; and Ohio State University, Columbus, Ohio
1
2
3
4
Ridker PM, Hennekens CH, Schmitz C, Stampfer MJ, Lindpainter K. PlA1/A2 polymorphism of platelet glycoprotein IIIa and risks of myocardial infarction, stroke, and venous thrombosis. Lancet 1997; 349: 385–88. Weiss EJ, Bray PF, Tayback MT, et al. The platelet glycoprotein IIIa polymorphism PlA2: an inherited platelet risk factor for coronary thrombotic events. N Engl J Med 1996; 334: 1090–94. Carter AM, Ossei-Gerning N, Grant PJ. Platelet glycoprotein IIIa PlA polymorphism in young men with myocardial infarction. Lancet 1996; 348: 485–86. Marenberg ME, Risch N, Berkman LF, Floderus B, de Faire U. Genetic
Vol 349 • April 12, 1997
5
susceptibility to death from coronary heart disease in a study of twins. N Engl J Med 1994; 330: 1041–46. Goldschmidt-Clermont PJ, Weiss EJ, Shear WS, et al. Platelets from PlA2(–) individuals bind more exogenous fibrinogen than platelets from PlA2(+) individuals. Blood 1996; 88: 26a.
colleagues are correct in postulating an association between HSV1 and AD. David S Latchman Windeyer Institute of Medical Sciences, Depar tment of Molecular Pathology, University College London Medical School, London W1P 6DB, UK
1
Herpes simplex virus and risk of Alzheimer’s disease SIR—Itzhaki and colleagues (Jan 25, p 241) report that the combination of herpes simplex virus type 1 (HSV1) in the brain and carriage of the apolipoprotein E ε4 (APOE-ε4) allele is a significant risk factor for Alzheimer’s disease (AD). This finding is provocative and will, hopefully, inspire further work, particularly since the investigators include only four nonAD individuals who had the APOE-ε4 allele. It is possible, therefore, that their findings are simply dependent on the APOE-ε4 allele being a significant risk factor for AD combined with the high frequency of HSV1 in the brains of elderly individuals with or without AD. Thus, the very high frequency of the APOE-ε4 allele in the patients with AD, together with the occurrence of HSV1 in all patients, would result in a high frequency of AD patients who were positive for APOE-ε4 and HSV1. Further studies that include a larger number of healthy individuals (controls) who carry the APOE-ε4 allele are needed to investigate whether such individuals show a much lower frequency of HSV1 infection than do carriers of APOE-ε4 who have AD. Nonetheless, the report by Itzhaki does provide the first tentative evidence of a link between HSV1 and AD. It is unfortunate, therefore, that the researchers chose to conclude the paper with the suggestion that their findings “call into question the proposed use of HSV1 as a vector for gene therapy”. This is clearly not the case. HSV1 is a human pathogen that produces cold sores in a wide range of individuals and a lethal encephalitis in a small number of people. Similarly, direct injection of HSV into the brain of animals produces severe encephalitis and death even at low doses of virus.2 All the laboratories involved in the development of HSVbased vectors for gene therapy are producing highly disabled viruses that contain several mutations that would prevent the replication or expression of virus gene products when introduced into animals or patients in gene therapy procedures.3,4 Given the highly disabled nature of these viruses, which is necessary to prevent the risk of cold sores or encephalitis, the risk that the viruses would produce AD is infinitesimally small, even if Itzhaki and
2
3
4
Itzhaki RF, Lin W-R, Shang D, et al. Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet 1997; 349: 241–44. Maclean AR, Fareed MU, Robertson L, Harland J, Brown SM. Herpes simplex virus type 1 deletion variants 1714 and 1716 pinpoint sequences involved in neurovirulence. J Gen Virol 1991; 72: 631–39. Coffin RS, Latchman DS. Herpes simplex virus based vectors. In: Latchman DS, ed. Genetic manipulation of the nervous system. London: DS Academic Press, 1995: 99–114. Fink DJ, DeLuca NA, Goins WF, Glorioso JC. Gene transfer to neurons using herpes simplex virus-based vectors. Ann Rev Neuroscience 1996; 19: 265–87.
Authors’ reply SIR—We agree that the number of healthy individuals with an APOE-ε4 allele is small. Unfortunately, it will be difficult to obtain specimens from a larger number of such individuals because the percentage of healthy people, especially of very elderly individuals, with this allele is low, and few normal brains are available in brain banks in the UK or USA. Furthermore, Latchman’s suggestion that APOE-ε4 on its own but not HSV1 is a risk factor is questionable. In the group that included 22% (10/46) of the AD patients who were HSV1-negative in brain, only one fifth possessed an APOE-ε4 allele, which argues against the latter alone being a significant risk; presumably, other unknown factors account for the disease in this group of patients. We analysed the hypothesis of simple multiplicative effects, but this was rejected in favour of the alternative: a synergistic effect. In addition, the highly significant difference between the allele frequencies of individuals who have cold sores and those who do not lends support to our proposal that the combination of HSV1 in brain and possession of an APOE-ε4 allele is damaging in the nervous system. Incidentally, we would like to emphasise a point about prevalence that was not made explicit in our report: the combination of HSV1 in brain and possession of an APOE-ε4 allele was found in 29 (63%) of the 46 patients with AD, compared with only two (5%) of the 44 healthy controls. Finally, our comment at the end of the report was merely a suggestion that caution should be exercised because of the possibility, even if very remote, that recombination between the resident latent HSV1 genome and the disabled
1101