Voyager's Scientific Theory is Consistent with Current Theories of Alzheimer's Disease

The purpose of this scientific summary is to provide an overview of Alzheimer's disease (AD) and the major hypotheses regarding the cause(s) and to describe how each might reasonably be attributed to alterations in luteinizing hormone (LH). Primary scientific literature in support of Voyager's conclusions is cited.

Alzheimer's disease (AD) is a neurodegenerative disease that ultimately leads to death in afflicted individuals. Previous estimates suggest that there are 4.5 million people with AD in the U.S. alone, many of whom remain undiagnosed. A consensus report published in The Lancet in December of 2005 (1) stated new statistics about the current prevalence of AD and how it will increase in the future. This report estimates that the number of AD patients will double every 20 years to 42.3 million cases by the year 2020 and to 81.1 million cases by the year 2040. A more conservative estimate of AD prevalence published in Alzheimer's and Dementia in 2005 (2) predicted that the annual cost of AD to Medicare and Medicaid alone would exceed a trillion dollars per year by mid-century and AD will consume 4 of every 10 Medicare dollars.

AD research encompasses many therapeutic approaches that hold promise, but no researcher or company can demonstrate that they have an approach that will act in a "disease modifying" role, i.e., addressing the root cause of AD. Current Phase III AD trials are few in number and are generally designed only to demonstrate modest decreases in the rate of cognitive decline among AD patients. Several theories exist regarding appropriate biological targets to use in evaluating new therapies for AD. Many therapies under development depend on the theory that ß-amyloid accumulation (diagnostically known as amyloid plaques) is the cause of AD (3) and that removing it will benefit AD patients. Others examine the depletion of estrogen associated with menopause as a trigger for AD in aging women (4) while another theory suggests that sustained or higher testosterone levels may provide benefit to men with AD (5).

Neurofibrillary tangles associated with the phosphorylation of the protein "tau", long time diagnostic hallmarks of AD, are also being investigated (6). Other scientists, including those at Voyager, believe that dysregulation of the cell cycle in neurons may promote the neuronal cell death that leads to AD and that other AD-associated events result from that dysregulation (7, 8, 9). However, no consensus exists about the cause of AD or how to slow or stop its progression.

AD is a multifaceted disease that has many biochemical and physiological aspects that provide credence to each of the AD-associated theories mentioned above. Since AD is, first and foremost, a disease of aging and is likely multifactorial, it is reasonable to hypothesize that a biochemical change associated with aging might be the trigger for AD. It would also follow that if one identified the major trigger of AD, then it might be able to explain other aspects of AD. Voyager’s scientific evidence to date supports the hypothesis that luteinizing hormone (LH) may be associated with several of the pathological processes that result in AD, and Voyager's scientific theory is congruent with many mainstream theories regarding how AD arises and how to effectively treat this disease.

In a paper published in the Journal of Biological Chemistry in May, 2004 (10) Voyager's science team reported that leuprolide treatment of mice dramatically and significantly reduced the concentrations of brain Aß42 by 40% after four weeks, and by 71% after eight weeks. This is an important point, which was also stated in the NeuroInvestment Research Newsletter December, 2005 issue: "Voyager's founders believe – and this is an important connection to standard ideology – that abnormal gonadotropin levels also contribute to beta-amyloid production." More recently, we reported that leuprolide not only decreases amyloid production in a mouse model of AD, but also significantly lowered the rate of cognitive decline in these mice (11).

Decreases in estrogen concentrations have long been studied as a potential contributor to AD. The "Women's Health Initiative Memory Study" published data in May, 2003 and June, 2004 (12, 13) suggesting that estrogen replacement therapy per se was not beneficial in AD, but a recent report in the Proceedings of the National Academy of Science (14) has reinvigorated conversation focused on the role of estrogen. With respect to Voyager's hypothesis, estrogen is viewed as a normal part of the hypothalamic-pituitary-gonadal (HPG) axis. In pre-menopausal women, endogenous estrogen regulates LH production, but this feedback regulation is disrupted after menopause i.e. reduced estrogen levels in aging women results in elevations of LH, the hormone that we believe is causative in AD. In other words, elevation in LH might be an underlying cause of the observation that estrogen depletion contributes to AD.

Testosterone, like estrogen, is a normal component of the HPG axis. In men, the circulating levels of free testosterone are known to decline with advancing age (5). This can lead to elevations in LH which, like in women, may be responsible for inducing the pathological changes seen in Alzheimer's disease. It was also reported that free testosterone concentrations were lower in men who developed AD, and this difference occurred before diagnosis. Elevated or sustained levels of testosterone in aging men could prove beneficial and may potentially result in reduced levels of LH in the areas of the brain susceptible to AD pathology.

Voyager's scientific hypothesis is that several components of AD pathology may result from the abnormal entry of neurons, which typically do not divide, into the cell division cycle. Instead of successfully completing cell division, these terminally differentiated neurons die, and this neuronal cell death is believed by Voyager scientists to produce the clinical deficits observed in AD patients. A substantial body of evidence indicates that LH is elevated in AD patients (15, 16) and LH has been shown to stimulate cell division. Others have demonstrated that neurons in the brains of AD patients express proteins associated with various stages of the cell division cycle (8, 9) which strongly suggests that attempts at neuronal division are occurring in AD brains. Peter Davies, a prominent AD researcher, recently published (June 2005) results showing that neuronal cell death in a mouse model of AD that was previously thought to be the result of a tau mutation was, in fact, the result of the re-expression of cell-cycle proteins and DNA synthesis. These results indicate that the neurodegeneration he observed was likely linked to incomplete cell-cycle entry by neurons (7). A report published in the January 2006 issue of The Journal of Neuroscience (17) and partially funded by the National Institutes of Health suggests that, "for unknown reasons, nerve cells affected by AD and many other neurodegenerative diseases start to divide before they die." The authors likewise note that "this abnormal cell division starts long before amyloid plaques or other markers of disease appear." As we have reported previously, we believe that LH is a stimulus that promotes neurons to attempt to divide and have demonstrated that LH is elevated in AD patients and is also present in brain structures that are pathologically affected by AD (18).


Voyager's hypothesis is becoming well known in the AD research community.  It is consistent with, and can be integrated with, other theories of the etiology of Alzheimer's disease and may ultimately contribute to a better understanding of the disease.  We anticipate that the potential value of our hypothesis will increase as additional preclinical work is published and when Voyager's current Phase II and III clinical trials are completed and reported.



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