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Progress Towards the Treatment and Prevention of Alzheimer’s Disease
Alzheimer's Research Center

INTRANASAL NERVE GROWTH FACTOR RESEARCH

While the treatment strategies discussed so far are promising and should benefit Alzheimer’s patients, they do not directly address the underlying neurodegenerative process that leads to the loss of brain cells in this disease. Ideally, we would like to have a natural medication that would not only protect brain cells from damage, but would also cause the brain to produce more of the chemical messenger, acetylcholine.

Surprisingly, a natural medication of this sort already exists. It is called nerve growth factor. Nerve growth factor is a natural protein produced by the human brain. Pharmaceutical companies have gone so far as to isolate the human gene for nerve growth factor and use that gene to produce large amounts of this potentially therapeutic protein for the treatment of Alzheimer’s disease.

Unfortunately, nerve growth factor is too large of a molecule to cross from the blood stream into the brain. Finding a solution to this drug delivery problem has been a major challenge for medical researchers. However, at the Alzheimer’s Research Center, we have shown that therapeutic proteins, when administered intranasally as nose drops, can enter the brain directly without ever entering the blood. This is possible because of the direct connection that exists between the brain and the nasal cavity, via olfactory nerves, which are necessary for sensing odors.

When we administered nerve growth factor as nose drops, we found that it too could enter the brain by this olfactory route. The US Department of Commerce has awarded us a patent on this new method of drug delivery. This is especially exciting since Italian researchers have recently shown that decreasing the level of nerve growth factor in mice causes the mice to develop Alzheimer's symptoms and pathology as they age. Even more importantly, intranasal nerve growth factor largely reversed the brain degeneration in these animals with Alzheimer's pathology and rescued their memory loss.

We have also demonstrated that another type of nerve growth factor called insulin-like growth factor-1 can be delivered to the brain following intranasal administration. This growth factor has potential as a treatment not only for Alzheimer's disease, but also for stroke and head injury. Studies in animal models of stroke show that intranasal treatment with this growth factor dramatically reduces brain damage and improves neurological function. While we have made a lot of progress, we still have a long way to go to prove that intranasal delivery of nerve growth factors will effectively protect the brain cells of patients with Alzheimer's, stroke and other neurological disorders.

ADULT STEM CELL RESEARCH

Adult stem cells, or cells which can differentiate into a variety of tissue specific cells, have been the focus of many recent neurological studies. A 2008 study revealed that neural stem cells exist in every part of the adult brain. Furthermore, the same study revealed that these stem cells are prevented from developing by chemical signals from near’by cells called astrocytes. Tapping into the brain’s intrinsic ability to regenerate itself is a promising stratergy for treating many brain disorders and injuries, including Alzheimer’s disease. California researchers have stimulated stem cells in the brains of adult animals to develop into new nerve cells using our intranasal method of delivering nerve growth factors. We are pursuing this approach and others using adult stem cells to develope better ways to treat Alzheimer’s disease and other brain disorders.

BRAIN BANK RESEARCH PROGRAM

The Dementia Brain Bank Research Program has been operated by the Alzheimer’s Research Center for more than 30 years. The Brain Bank has collected over 2,500 brains obtained from individuals enrolled in our autopsy program who suffered from some form of dementia. It is one of the world’s largest collections of brain tissue, which contributes to research on the neurochemistry, physiology, and diagnosis of dementing illnesses. In conjunction with the brain tissue itself, clinical records and a family history are obtained for each donor in order to better understand each dementing illness and to work towards the improvement of diagnosing, treating, and preventing these diseases. To date, the Brain Bank Research Program has resulted in a number of important publications and findings. One highlight of this research was the discovery that the APOE allele is altered in the brains of patients with Alzheimer’s disease. This finding alone resulted in thousands of publications from other researchers on this topic. Also it was discovered that glucose uptake and utilization is decreased in the brains of Alzheimer’s patients, which contributed to the discovery that intranasal insulin improved memory in patients with the disease. It is evident that the Brain Bank has and will play a critical role in unlocking the mystery behind Alzheimer’s disease and other dementing illnesses.

RESEARCH ABOUT APOE

Alterations in a gene that codes for the protein APOE are present in the majority of cases of Alzheimer's disease with an onset after 60 years of age. In 1991, we, along with our colleagues, showed that alterations in the APOE protein could be seen in the areas of the brain affected by Alzheimer's disease. While a blood test for this genetic alteration has been developed, we do not recommend that individuals take the test, as interpretation of its results are as yet unclear. People who have this genetic alteration may exhibit decreased metabolism in the areas of the brain affected by Alzheimer's disease as many as 5-10 years or more before they actually have symptoms of the disease such as memory loss. This discovery could help researchers determine if new experimental treatments are effective at delaying or preventing the onset of dementia symptoms.

APOE functions to transport cholesterol into the brain. Recent studies have shown that patients who took cholesterol-lowering medications, called statins, were 70% less likely to develop dementing illnesses like Alzheimer's disease. It will be interesting if further research can demonstrate that lowering cholesterol can help prevent Alzheimer's disease.