Alzheimer’s disease affects an estimated 5 million individuals in the US and causes a devastating loss of cognitive function due to the buildup of beta-amyloid and tau proteins in the brain. Previous efforts to combat this disease have focused on developing drugs that target beta-amyloid, but such treatments have been unsuccessful in patients so far. Several exciting new approaches for treating Alzheimer’s are currently being tested in clinical trials in the US and Europe. These trials will assess the efficacy of an anti-viral drug that is normally used to treat herpes, and a new vaccine that generates antibodies against tau protein.
Alzheimer’s disease was first identified in 1906 and is the most common cause of dementia, responsible for an estimated 60–70 percent of dementia cases. Alzheimer’s predominantly affects the elderly, but approximately 5 percent of cases involve early-onset disease (prior to the age of 65). The predominant symptoms of Alzheimer’s are a loss of memory and other intellectual capacities, which must be severe enough to interfere with everyday functioning. Mood swings and behavioral difficulties are also predominant symptoms. As the disease progresses, motor functions can also be impacted, inhibiting the ability of patients to speak, swallow, and even walk. Affected individuals typically survive between 4–20 years beyond the time that their symptoms become noticeable to others, with an average survival time of 8 years.
Research into the causes of Alzheimer’s has revealed that two proteins, beta-amyloid and tau, play a key role in disrupting the neural processes that underlie memory and other cognitive abilities. Beta-amyloid normally acts to combat oxidative stress, regulate cholesterol transport, and fight off bacteria in the brain. In Alzheimer’s, however, beta-amyloid is overproduced. The excess protein forms clumps, or plaques, around neurons that can interfere with the transmission of nerve impulses. Tau is found in abundance in neurons and normally acts to stabilize cell proteins called microtubules in neuronal axons. In Alzheimer’s disease, defective forms of tau are produced, often containing large numbers of attached phosphate groups, termed hyperphosphorylated tau. Defective tau fails to stabilize microtubules, and instead binds together into insoluble aggregates or “tangles” of protein. The buildup of these neurofibrillary tangles inside of neurons, combined with amyloid plaques surrounding neurons, disrupts cell-to-cell communication in the brain.
Current therapies for Alzheimer’s include drugs that treat the symptoms of dementia by regulating neurotransmitter levels; however, none of these treatments directly addresses the cause of the disease. Research efforts have focused on finding a drug that can prevent the buildup of plaques by interfering with beta amyloid synthesis and aggregation. Unfortunately, despite promising preclinical data from animal studies, these drugs failed to produce results in humans or had devastating side effects. For example, one anti-beta-amyloid vaccine caused meningoencephalitis or inflammation of the brain tissue and surrounding membranes. This side effect may have resulted from the reaction of the vaccine with beta-amyloid normally present in the walls of blood vessels. Such serious side effects were cause for cessation of the trial, and researchers have subsequently turned their attention to other possible treatments.
A research team led by Hugo Lövheim from the Department of Community Medicine and Rehabilitation and the Unit of Geriatric Medicine at Umeå University in Sweden is piloting the first clinical study to address the effect of a herpes virus drug on Alzheimer’s disease. Lövheim’s group previously showed that infection with herpes virus was correlated with an increased risk of Alzheimer’s disease. People who tested positive for antibodies associated with the reactivated form of herpes simplex virus type 1 (HSV-1 anti-IgM) had double the risk of developing Alzheimer’s. Thus, the researchers surmised that brain signaling pathways activated by the virus might trigger the disease, and conversely, that anti-viral drugs might reverse disease symptoms.
The VALZ-Pilot study is currently recruiting participants with Alzheimer’s to investigate the effects of Valaciclovir, sold by the brand name Valtrex, a drug typically prescribed to treat genital herpes, cold sores, and shingles. Thirty-six participants will receive four weeks of drug treatment. Markers in the spinal fluid will be examined to assess the effect of the drug on several Alzheimer’s disease parameters, including levels of tau protein. A subset of subjects will also undergo positive emission tomography (PET) brain imaging analysis. By using a tracer that accumulates in cells with active herpes infection, this methodology can potentially detect this infection in the brains of Alzheimer’s patients.
A second new approach for treating Alzheimer’s, spearheaded by Petr Novak and colleagues at the Karolinska Institutet in Sweden, is the generation of a vaccine that targets the tau protein. Previous vaccine treatments for Alzheimer’s, which have thus far proven unsuccessful, focused only on beta-amyloid. The new vaccine, AADvac1, will prompt the body to generate antibodies against tau. The production of anti-tau antibodies will hopefully direct the immune system to clear tau protein from inside brain cells, similar to the way it fights off viruses and bacteria.
Developing a tau vaccine wasn’t easy; tau is a protein also found in healthy brains, and thus the removal of “healthy tau” by a vaccine could have negative side effects. The researchers compared differences in the structure of the healthy and pathological tau proteins, and identified what they call the “Achilles heel” of the abnormal protein. They were then able to create a vaccine that recognizes this feature of the abnormal protein, yielding treatment specificity for the disease-causing tau.
So far the AADvac1 vaccine is in phase 1 of clinical trials, which involves administration of the drug to healthy volunteers to assess side effects, but does not address efficacy. No serious side effects have been observed thus far, and volunteers have experienced only minor reactions at the injection site, similar to other types of vaccines. The lack of side effects is a promising first step. Moreover, the trial has also demonstrated the effectiveness of the drug to elicit an immune response, which is a critical factor for its success. These promising preliminary data provide much-needed hope for Alzheimer’s patients and their families.
References
Hippius H, Neundörfer G. (2003) The discovery of Alzheimer’s disease. Dialogues Clin Neurosci. 5(1):101-8. PMID: 22034141.
Marciani D. (2016) A retrospective analysis of the Alzheimer’s disease vaccine progress – The critical need for new development strategies. J Neurochem. 137(5):687-700. doi: 10.1111/jnc.13608.
Novak P, RSchmidt R, Kontsekova E, Zilka N, Kovacech B, Skrabana R, Vince-Kazmerova Z, Katina S, Fialova L, Prcina M, Parrak V, Dal-Bianco P, Brunner M, Staffen W, Rainer M, Ondrus M, Ropele S, Smisek M, Sivak R, Winblad B, Novak M. (2016) Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase 1 trial. The Lancet Neurology. S1474-4422(16)30331-3. doi: 10.1016/S1474-4422(16)30331-3.
Lövheim H, Gilthorpe J, Adolfsson R, Nilsson L, Elgh F. (2014) Reactivated herpes simplex infection increases the risk of Alzheimer’s disease. Alzheimers Dement. 11(6):593-9. doi: 10.1016/j.jalz.2014.04.522.
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