Alzheimer’s disease is a degenerative and slowly progressive brain disease that affects multiple cognitive functions including memory, language, orientation, planning and judgment. It is the most common cause of dementia. Although age remains the most common risk factor, there are other factors such as family history and genetic susceptibility. There are also various forms of the disease such as young onset Alzheimer’s disease, posterior cortical atrophy, primary progressive aphasia and other less common types of the disease. There are currently 5.8 million Americans with the disease and this is just the reported cases and if the trend continues, there will be more than 14 million Americans with the disease by 2050. It is the 6th leading cause of death among all Americans and 4th among the elderly population (age 65 or older). It has an associated annual cost of 290 billion dollars and by 2050 1.1 trillion. Given the statistics noted above, today more than ever there is an urgency to find more effective treatments to stop or slow the progression of this devastating disease.
Since 1994 we have had a total of six medicines that have been approved by the Food and Drug Administration for use in Alzheimer’s disease. These include, Tacrine (Cognex), Donepezil (Aricept), Rivastigmine (Exelon capsule and patch forms), and Galantamine (Razadyne), collectively a class of cholinesterase inhibitors, Memantine (Namenda), an NMDA receptor antagonist and Axona, a medical food. Unfortunately, these drugs are only beneficial for symptom improvement and do not offer a lasting benefit nor do they modify the course of the disease. The reason behind developing cholinesterase inhibitors was the discovery of acetylcholine deficiency due to the effect of the disease in cholinergic system. Multiple cholinomimetic drugs were tested but were not successful because acetylcholine-like substances would not survive the stomach acidity, and hence would not get to their destination, the brain. Further research finally determined that the cholinesterase inhibitor, an indirect way of delivery of these compounds, proved to be the most effective way to enhance cholinergic stimulation.
There have been hundreds of drugs tested since then, including multiple calcium channel blockers, serotonin antagonists and neurotrophic factors, but unfortunately none have been approved for one reason or another such as safety concerns or lack of efficacy. We are still not certain about the mechanism or mechanisms that lead to the neuronal damage leading to the Alzheimer’s disease development. This is because the pathological findings seen in patients with Alzheimer’s disease brain is also seen in some individuals who do not develop Alzheimer’s disease. Many theories exist such as amyloid hypothesis, inflammation, tau hypothesis and multiple other possible ways the disease is developed. So far amyloid and tau proteins as possible initiating factors have gained more legitimacy. This combined with the development of APOE genes as well as markers of inflammation and the advancements in brain Amyloid PET imaging, and spinal fluid analysis have improved our ability to identify the susceptible individuals. This will allow us to develop drugs that will target this population so we can develop more effective treatments through controlled clinical trials. We are searching for disease modifiers, drugs that stop or slow the progression of the disease.
Despite recent disappointments with some anti-amyloid antibodies and multiple beta amyloid secretase (BASE) inhibitors, there are several promising drugs that are currently under investigation as disease modifiers that seem to be safe and well tolerated. Currently, there are several anti-amyloid antibodies, anti-tau antibodies, anti-inflammatory agents, antibiotics, anti-cancer drugs and receptor modulators that are in various stages of development. The effectiveness and safety of these drugs can only be observed through carefully crafted and controlled clinical trials.
In addition to experimental drug trials, our understanding of non-medical approaches has significantly improved. We now know that reducing certain unhealthy diets such as various forms of carbohydrates, alcohol, carbonated beverages, high fat content foods, such as fried meals have significant beneficial effects. Careful monitoring and treatment of heart disease, hypertension, dyslipidemia and diabetes during routine physical check-ups is generally a good practice to prevent potential cardiovascular diseases. We have also learned about the benefits of mental and physical and mental stimulating activities such as regular physical exercise and mental activities such as cross word puzzles, word search, Sudoku and playing cards.
As our understanding of the cause (s) of Alzheimer’s disease improves, we will be able to discover more markers such as blood tests and other modalities to better understand this disease and subsequently find more effective treatments. I believe that the ideal treatment for Alzheimer’s disease may be a combination or a cocktail of drugs with different mechanisms of action to address the multitude of insults to the brain that lead to the development of the disease. My advice to everyone affected by this disease is to keep an open mind about research and give themselves or their loved ones a chance to explore research options. This will allow the scientific community to develop more effective treatments. The Alzheimer’s Association and Clinicaltrials.gov are excellent sources for information to learn about the research programs and the closest research center near you.
M. Reza Bolouri, MD
Alzheimer’s Memory Center
Charlotte, North Carolina
