Alzheimer’s Disease Vaccine on the Horizon




Alzheimer’s disease (AD) is a devastating illness that causes memory loss and intellectual impairment. AD currently afflicts an estimated 18 million people throughout the world, but it affects countless more friends, caregivers, and relatives. More than 1 in 13 people over the age of 65 have signs and symptoms consistent with AD. Unfortunately, the cause of AD is still unclear a century after its discovery, and the disease is largely untreatable.

While the causes of AD are not well-defined, a few known risk factors have been identified: increasing age, Down’s syndrome, and head injury. There is a strong genetic component to some cases of AD, but many cases are sporadic, with no significant family history. Mounting evidence now suggests that infectious agents may play a role in the development of AD, opening the door to new treatment modalities.

Infectious agents are normally known for causing acute illnesses, but some have been implicated as the cause of chronic diseases, including human papillomavirus in cervical cancer and the bacterium Helicobacter pylori in stomach ulcers, which has led to the use of vaccines and antimicrobial agents to treat chronic diseases. In the last decade, Herpes simplex virus type 1 (HSV1) has been increasingly associated with the development of AD.

HSV1 is ubiquitous, identified in approximately 90% of adults. Normally, an infection with HSV1 occurs in infancy, but the virus remains lifelong in the peripheral nervous system in a latent, inactive state. HSV1 can be reactivated later in life by stress, immunosuppression, fever or ultraviolet light exposure; HSV1 is the virus that causes cold sores. Researchers postulate that if HSV1 reaches the brain, the virus could cause damage consistent with AD. Likewise, HSV1 is already identified as the cause of herpes simplex encephalitis, a rare but serious brain disorder, which leaves survivors with memory loss and a loss of cognitive function, just as AD does.

HSV1 does not cause AD on its own. There are likely host factors that alter the risks for developing AD. Interestingly, a genetic component — the type 4 allele of the apolipoprotein E gene, which normally transports lipids in the body and repairs tissue damage — confers a high risk of AD when associated with HSV1. (The same genetic component is an increased risk factor for cold sores.)

Two hallmarks of AD are the presence of amyloid plaques and neurofibrillary tangles in the brain. Beta-amyloid, the primary component of the plaques, accumulates in the presence of HSV1 infections. Further, 90% of plaques evaluated from AD brains contained HSV1, and 72% of the virus DNA was associated with plaques; in normal, aged brains, which contain amyloid plaques at a much lower frequency than AD brains, 80% of the plaques contained HSV1, but only 24% of the viral DNA was plaque-associated. In normal brains, it is likely that there is a lesser production or greater removal of beta-amyloid, so it is less likely that HSV1 would be able to interact destructively inside the brain. Basically, HSV1 infection likely induces changes in gene expression in the brain, through its inflammatory and oxidative processes, that are damaging to the brain.

The only current pharmacological therapies approved for AD are acetylcholinesterase inhibitors and N-methyl-D-aspartic acid receptor inhibitors, which demonstrate symptomatic improvement, but do not treat the underlying cause of AD. The proposed involvement of HSV1 in AD has led to the possibility of the first potentially disease-modifying treatments in AD. Antiviral agents, such as acyclovir and valacyclovir, may be beneficial in preventing disease progression in AD patients. These agents inhibit the synthesis of viral DNA, preventing its spread throughout the body and the damage it causes. (Acyclovir is also being evaluated in the treatment of multiple sclerosis, owing to another herpes virus implicated in the development of that disease.) Alternatively, a vaccine to prevent the reactivation of HSV1 and prevent AD altogether is being evaluated in human trials. Anti-viral agents are the first attempt to prevent the pathogenesis of AD, rather than just treat the symptoms, offering hope to millions of current and future AD sufferers and their families.

References

Chackerian B (2010). Virus-like particle based vaccines for Alzheimer disease. Human vaccines, 6 (11) PMID: 20864801

Chackerian B, Rangel M, Hunter Z, & Peabody DS (2006). Virus and virus-like particle-based immunogens for Alzheimer’s disease induce antibody responses against amyloid-beta without concomitant T cell responses. Vaccine, 24 (37-39), 6321-31 PMID: 16806604

Hill JM, Zhao Y, Clement C, Neumann DM, & Lukiw WJ (2009). HSV-1 infection of human brain cells induces miRNA-146a and Alzheimer-type inflammatory signaling. Neuroreport, 20 (16), 1500-5 PMID: 19801956

Itzhaki RF, & Wozniak MA (2006). Herpes simplex virus type 1, apolipoprotein E, and cholesterol: a dangerous liaison in Alzheimer’s disease and other disorders. Progress in lipid research, 45 (1), 73-90 PMID: 16406033

Lukiw WJ, Cui JG, Yuan LY, Bhattacharjee PS, Corkern M, Clement C, Kammerman EM, Ball MJ, Zhao Y, Sullivan PM, & Hill JM (2010). Acyclovir or Abeta42 peptides attenuate HSV-1-induced miRNA-146a levels in human primary brain cells. Neuroreport, 21 (14), 922-7 PMID: 20683212

Sabbagh, M., & Berk, C. (2010). Latrepirdine for Alzheimer’s disease: trials and tribulations Future Neurology, 5 (5), 645-651 DOI: 10.2217/fnl.10.53

Wozniak MA, Mee AP, & Itzhaki RF (2009). Herpes simplex virus type 1 DNA is located within Alzheimer’s disease amyloid plaques. The Journal of pathology, 217 (1), 131-8 PMID: 18973185

Wozniak, M., & Itzhaki, R. (2010). Antiviral agents in Alzheimer’s disease: hope for the future? Therapeutic Advances in Neurological Disorders, 3 (3), 141-152 DOI: 10.1177/1756285610370069

  • But are the plaques and tangles a result of the fight against AD or the result of AD?
    http://www.aarp.org/health/conditions-treatments/info-05-2010/alzheimers_disease.2.html

  • Christine

    I had read another article that said the bacterium Helicobacter pylori, which causes stomach ulcers has been found in people’s brains and may cause AD. And I read the book “Back to Eden” which said that cooking with aluminum cookware causes AD.

    Perhaps all of these things can cause AD?

  • Plaques and tangles in Alzheimer’s disease are heavily enriched in herpes simplex binding proteins. They would appear to be the direct result of a battle between herpes simplex and the immune system, which may well have killed the virus, but at the expense of immune and inflammation related destruction of neurones. Many Alzheimer’s disease susceptibility genes are also involved in the herpes simplex life cycle References . This suggests that the virus could cause Alzheimer’s disease in genetically susceptible individuals.

    The plaques and tangles argument is illustrated in this publication

Jennifer Gibson, PharmD

Jennifer Gibson, PharmD, is a practicing clinical pharmacist and medical writer/editor with experience in researching and preparing scientific publications, developing public relations materials, creating educational resources and presentations, and editing technical manuscripts. She is the owner of Excalibur Scientific, LLC.
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