. Statins lower the risk of developing Alzheimer's disease by limiting lipid raft endocytosis and decreasing the neuronal spread of Herpes simplex virus type 1. Med Hypotheses. 2005;64(1):53-8. PubMed.


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  1. Jim Hill and colleagues propose an interesting idea based on our work showing that HSV1 is a risk for AD when present in brains of carriers of ApoE4 (Itzhaki et al., 1997). They suggest that the preventive action of statins in AD is due to their inhibition of the spread of the virus through the nervous system. They theorize that statins disrupt the formation of lipid rafts, which in turn stops the spread of HSV1 in the nervous system (lipid rafts, of which cholesterol is an essential component, are a requirement for entry of HSV1, as shown recently by Bender et al., 2003). However, one should add a proviso: their concept depends on whether statins will definitely be shown to be protective against AD; this still seems uncertain, judging by some reports at the international AD Conference in Philadelphia, and by some recent publications (Caballero et al., 2004).

    Surprisingly, Hill et al. discuss ApoE in some detail, yet they do not suggest any role for the protein ApoE in the HSV1-lipid raft entry mechanism. In fact, a possible ApoE effect—determining the level of cholesterol in lipid rafts (as it does in plasma)—is suggested by the finding that in ApoE-transgenic mice the amount of cholesterol is about twofold higher in certain components of the plasma membrane in ApoE4 than in E3 animals (Hayashi et al., 2002). If this is true of humans also, HSV1 might enter and spread more readily in brain of ApoE4 carriers.

    The suggestion of Hill et al. hinges on the involvement of HSV1 in AD. We and Brian Balin recently commented on the support for a role of infectious agents in AD afforded by the intriguing similarities among the neuropathology of HIV, measles virus infection, Chlamydia pneumoniae, and that of AD, as shown by Pulliam et al. and several other groups. Yet another connection between HIV and HSV1 relates to their modes of entry into cells, as mentioned in one of the papers quoted by Hill et al.: HIV, like HSV1, requires cholesterol for fusion and entry (Bender et al.). Indeed, to account for the role of ApoE4 in the dementia and peripheral neuropathy caused by HIV (pre-AIDS) (Corder et al., 1998), we previously pointed out another similarity in entry in that both viruses—like ApoE—bind to HSPG in the cell surface (Itzhaki et al., 1997). Thus, protein and virus might compete for HSPG, with ApoE4 competing less well than the other ApoE isoforms, hence allowing more entry and spread of the virus. This concept is supported by our discovery that ApoE determines outcome of infection in four other diseases caused by infectious agents, all of which enter cells via HSPG or a specific ApoE receptor (see e.g., Itzhaki et al., 2004). Possibly, such a mechanism might act concurrently with another involving lipid rafts and ApoE.

    One last point: the number that Hill et al. quote for AD sufferers in the U.S. seems to have lost a decimal point! The paper they cite (Hebert et al., 2003) states 4.5 million rather than 45 million, or almost one sixth of the U.S. population.


    . Specific association of glycoprotein B with lipid rafts during herpes simplex virus entry. J Virol. 2003 Sep;77(17):9542-52. PubMed.

    . Do statins slow down Alzheimer's disease? A review. J Clin Pharm Ther. 2004 Jun;29(3):209-13. PubMed.

    . HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy. Nat Med. 1998 Oct;4(10):1182-4. PubMed.

    . Cholesterol is increased in the exofacial leaflet of synaptic plasma membranes of human apolipoprotein E4 knock-in mice. Neuroreport. 2002 Mar 25;13(4):383-6. PubMed.

    . Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol. 2003 Aug;60(8):1119-22. PubMed.

    . Statins lower the risk of developing Alzheimer's disease by limiting lipid raft endocytosis and decreasing the neuronal spread of Herpes simplex virus type 1. Med Hypotheses. 2005;64(1):53-8. PubMed.

    . Herpes simplex virus type 1 in brain and risk of Alzheimer's disease. Lancet. 1997 Jan 25;349(9047):241-4. PubMed.

    . Infiltration of the brain by pathogens causes Alzheimer's disease. Neurobiol Aging. 2004 May-Jun;25(5):619-27. PubMed.

    . HIV-1 Tat inhibits neprilysin and elevates amyloid beta. AIDS. 2005 Jan 28;19(2):127-35. PubMed.

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  1. The Pathogen Hypothesis