Viruses and Dementia, and the Role of Apolipoprotein E (ApoE)
By Ruth Itzhaki, University of Manchester Institute of Science and Technology
Posted 15 June 2002
Note: This essay was adapted from an article in the Journal of Alzheimer's Disease (vol. 4, no. , special issue on "Challenging views of Alzheimer disease") and is presented here with the permission of the publisher.
We examined the potential roles of defective DNA repair, aluminum, and viruses, in particular herpes viruses in the development of AD. Herpes simplex virus type 1 (HSV1) resides in the PNS of most humans in a latent form. In herpes simplex encephalitis (HSE), a very rare acute infection of the brain, HSV1 affects the same regions of the brain as those most damaged in AD. However, whether herpes viruses (or any other viruses) are present in the CNS in the absence of an acute infection was previously uncertain. Earlier studies examining this question used in situ hybridization, a relatively insensitive method that yielded conflicting results (Itzhaki, 1994). Using polymerase chain reaction (PCR), we found that HSV1 DNA is present in a latent form in most aged brains-those of normal people as well as those of AD patients (Jamieson et al., 1991, et seq.). In younger subjects, in contrast, we detected HSV1 in fewer than 10% of brains, so we suggested that in old age, the virus can reach the brain because of the decline in the immune system (Itzhaki et al., 1993; Lin, W-R et al., in preparation).
Subsequently, several other groups confirmed our PCR detection of HSV1 DNA in the brain of a substantial proportion of people (Bertrand et al., 1993; Baringer and Pisani, 1994; Gordon et al., 1996). Despite the virus being resident in many aged normal brains, we realized that it could be a factor in AD if it were acting in conjunction with a genetic factor. The obvious candidate gene was ApoE, which is known to be a susceptibility factor for AD, yet is neither essential nor sufficient for its development. We therefore investigated the ApoE genotypes of our subjects (61 AD patients and 48 age-matched controls) and found that the combination of HSV1 DNA in the brain and carriage of a type-4 allele of ApoE conferred a strong risk of development of AD (odds ratio, 12.0, 95% C.I., 3.44-42.06), accounting for about 60% of the AD patients we examined (Itzhaki et al., 1997; Lin et al., 1998). Neither viral DNA nor ApoE-e4 was a risk factor on its own. This interdependence of infection outcome and a genetic factor was strongly and independently supported by our finding that ApoE-e4 is a risk factor for cold sores (p<0.0001) (Itzhaki et al., 1997; Lin et al., 1998). We conclude that in the PNS and brain, the virus reactivates under conditions of stress or immunosuppression and causes more damage in ApoE-e4 carriers than in those with the other ApoE alleles. Subsequently, another study reported a similar HSV1-ApoE connection in AD (Itabashi et al., 1997), and a third showed a similar trend (Beffert et al., 1998).
There are several other studies demonstrating that lipoproteins or their components interact with a variety of viruses (see review by Dobson and Itzhaki, 2001). Of particular relevance is a study of HIV-infected subjects (pre-AIDS) showing that the onset of dementia (reversible) and peripheral neuropathy were more frequent in ApoE-e4 carriers (Corder et al., 1998). Further, we have found that another ApoE allele, ApoE-e2, is a risk factor for HSE (Lin et al., 2001a). Even more strikingly, we recently discovered that ApoE determines the extent of damage in liver disease caused by hepatitis C virus (HCV) (which infects 170 million people worldwide), type 4 being highly protective. On comparing ApoE-e4 of those with very mild versus very severe damage liver damage, the odds ratio was 0.091, C.I. 0.019-0.440 (Wozniak MA et al., Hepatology, in proof). Thus, it appears that ApoE affects the extent of damage in at least five disorders known to be caused by three very different viruses: cold sores, HSE, two neurological disorders in HIV patients, and HCV-induced liver damage. Although it is not known if a virus initiates AD, these very strongly (even if indirectly) support our contention that the combination of ApoE and HSV1 in brain is a major risk factor for AD development.
We recently obtained independent evidence, using a completely different approach, that HSV1 is indeed present in brain, and that it reactivates at some stage. As a marker of viral reactivation, we sought antibodies to HSV1 that are present in the CSF, as these are known to be very long-lived after HSE. (We checked that they were not due to leakage from serum across the blood-CSF barrier.) We found these antibodies in almost half of 27 AD patients and of 13 aged normals from whom paired CSF and serum samples were available (Wozniak et al., in preparation). No intrathecal antibodies were detectable in the case of four children (in whose brains HSV1 would almost certainly be absent-indicating that artefactual cross-reaction with a human protein was not occurring). These results substantiate our PCR studies showing the presence of HSV1 DNA and that reactivation occurs in both AD patients and age-matched controls, causing an acute (and presumably localized) infection. They show also that the whole genome must be present-as did our detection previously, by RT-PCR, of latency-associated transcripts. The greater damage in brain of ApoE-e4 carriers might perhaps result from a greater frequency of reactivation or from a lesser efficiency of repair after viral damage.
Recently, we found that human herpes virus type 6 (HHV6) is present in a much higher proportion of brains from AD patients than of age-matched controls, whereas HSV type 2 and cytomegalovirus (CMV) (Lin et al., 2002b) are present in relatively few brains from AD and normal patients. Varicella zoster virus is not present in either AD or normal brain tissue (Lin et al., 1997). In the case of vascular dementia (VaD), we detected CMV DNA in brain of a much higher proportion of VaD patients than of age-matched normals (Lin et al., 2002a). However, whether HHV6 is a risk factor for AD and CMV a risk factor for VaD is uncertain, as each could be a consequence of disease rather than a causative agent. Nonetheless, it is very intriguing that HHV6 can augment viral damage-e.g., of HSV1 on rabbit cornea and HIV on cultured cells-while CMV has recently been implicated quite strongly as a possible risk factor in coronary artery disease-a disease which shares a number of risk factors with VaD. We looked also for evidence of chlamydia DNA in VaD brains, as this bacterium has been proposed as a risk factor in heart disease, but we did not detect it in any of 19 brains (Wozniak et al., submitted). If these viruses are risk factors for AD or VaD, respectively, a yet unanswered question is whether or not either acts in conjunction with a genetic factor (other than ApoE).
Another recent result of ours is that vaccination of HSV1-infected mice with mixed HSV1 glycoproteins protects them against the establishment of viral latency in brain (Lin et al., 2001b).
The significance of our results is not only the intriguing dependence of viral damage on a host factor in several diseases, but also the possibility that at least some cases of AD could be prevented by vaccination, and that antiviral treatment could prevent deterioration in those already afflicted.
This work has been supported over the years by grants from Research into Aging, Humane Research Trust, Sir Halley Stewart Trust, Wellcome Trust, Remedi, Dr. Hadwen Trust, and carried out over those years in this lab mainly by GA Jamieson, W-R Lin, CB Dobson, MA Wozniak, and A Cookson.
More Recent Reference
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