Background

Alzheimer’s disease (AD) is an intractable, chronic and progressively incapacitating disease characterized by the degeneration and death of several types of neurons in certain regions of the brain.  Patients affected by the disease initially suffer loss of memory, then a decline of intellectual abilities severe enough to interfere with work and activities of daily living, followed by severe dementia and, finally, death.  This illness, currently affecting an estimated 4.5 million people in the United States, and approximately ten million people worldwide, is a leading cause of death behind cardiovascular disease and cancer. While the disease is most common in the elderly, affecting nearly 10% of people age 65 and older and up to 50% of people age 85 and older, it has been diagnosed in patients in their 40’s and 50’s.*

Alzheimer’s disease was first described in 1907 by Dr. Alois Alzheimer, a German psychiatrist who discovered large numbers of unusual microscopic deposits in the brain of a demented patient upon autopsy.  These deposits, called amyloid plaques and neurofibrillary tangles, are highly insoluble protein aggregates that form in the brains of AD patients in particular regions, including those involved with memory and cognition.  Generally, amyloid plaque is deposited on the surface of neurons, whereas neurofibrillary tangles are formed within neurons.  The plaques and tangles are associated with degeneration and loss of neurons.  The actual loss of neurons, as well as the impaired function of surviving neurons, is generally believed to be the key neuropathological contributors to the memory loss and dementia that characterizes Alzheimer’s disease.

Applied NeuroSolutions’s core technology in the AD field is based on the work of its founding scientist Dr. Peter Davies and his colleagues at the Albert Einstein College of Medicine.  Much of Dr. Davies’ AD research has been involved within an abnormal form of a protein called tau that normally serves to stabilize microtubules, the transit system in nerve cells that directs molecules to their destinations.  Excessive phosphorylation of tau prevents it from stabilizing microtubules.  This internal neuronal damage leads to the development of the paired helical filaments and neurofibrillary tangles, which are contributing factors to the eventual death of the neurons related to Alzheimer’s disease, and is one of the hallmark pathologies associated with AD.  There is a high correlation among the presence of neurofibrillary tangles and cognitive decline in AD.

* Alzheimer’s Association, February 2006

Diagnostic Program

Alzheimer’s disease, at present, can be conclusively diagnosed only by histological examination of the brain by biopsy or autopsy.  The diagnosis of patients suspected of having AD is therefore typically made through a process of elimination, by conducting neurological and psychiatric examinations, extensive laboratory tests and a brain scan to rule out other conditions (such as stroke, brain tumor, or depression) with similar symptoms.  The definitive AD predictive accuracy of such exams is generally in the range of 75-80%.  Costs to patients for such testing currently runs anywhere from $1,000 - $4,000.  A simple, predictive, accurate and cost effective diagnostic assay would therefore meet a tremendous medical need.

Applied NeuroSolutions has completed the development of a diagnostic assay utilizing cerebrospinal fluid (CSF).  To date, the Company has completed numerous studies comprising in excess of 2,500 CSF samples utilizing this assay.  These studies were designed to test the assay’s ability to differentiate patients diagnosed with AD from patients diagnosed with other forms of dementia and relevant neurological diseases, including major depression, as well as healthy controls.  These studies have shown the ability of the assay to correctly identify the patients diagnosed with AD with an overall sensitivity and specificity in the 85% to 95% range.  The studies have been published in peer reviewed scientific journals such as Neuroscience Letters, Archives of Neurology, Annals of Neurology, Archives of General Psychiatry, Journal of Internal Medicine, Neurobiology of Aging, Neurology, and American Journal of Psychiatry.

These data suggest that the phosphotau may represent an excellent biochemical marker for AD.  It detects a characteristic feature of pathophysiology, may allow one to track disease progression and accurately discriminates between AD patients and neurological controls.  Several pharmaceutical companies have utilized the Company’s CSF phosphotau assay as a biomarker in the clinical development of therapeutics to treat AD.

Therapeutic Program

The Company’s long-range goal is to discover and develop novel therapeutics to treat AD.  Work is being conducted utilizing an in-vitro screen Dr. Davies has developed that could lead to the discovery of a therapeutic to stop the progression of Alzheimer’s disease.  The basis for this screen is the discovery of a common pathway that leads to the development of both the neurofibrillary tangles and amyloid plaques.

The market potential for a drug to effectively treat Alzheimer’s disease is extremely large. Currently there are only five drugs approved in the U.S. to treat AD.  Four of these drugs are cholinesterase inhibitors and one is an NMDA receptor antagonist.  These drugs have limited beneficial effects in treating symptoms associated with AD and are not able to arrest the progression of the disease.


Transgenic Mice Model

To date, no accepted animal model for AD has been developed.  However, recently Dr. Peter Davies, through collaboration with a researcher at Nathan Klein Institute (“NKI”), has produced a transgenic mouse that develops neurofibrillary tangles, one of the two hallmark pathologies of Alzheimer’s disease.  The pathology in these mice is Alzheimer-like, with hyperphosphorylated tau accumulating in cell bodies and dendrites leading to the production of neurofibrillary tangles.  In addition, these transgenic mice have exhibited extensive neuronal death, which accompanies the tau pathology.  These new transgenic mice could be used for testing the efficacy of therapeutic compounds.  Several pharmaceutical and biotechnology companies have expressed interest in acquiring access to these transgenic mice for testing their therapeutics.  The Company and NKI are currently marketing these mice to researchers.