Advances in the Treatment and Prevention of Alzheimer’s Disease
Prevention is not a new concept. Agerelated neurodegenerative diseases like late-onset Alzheimer’s develop over the years, due to a combination of genetic, environmental and lifestyle factors. It has become clear that some environmental and behavioral risk factors are modifiable. According to the Lancet Commission, an estimated 4/10 cases of Alzheimer’s Disease (AD) are preventable. Furthermore, each person has a specific risk profile, which highlights the importance of developing evidence-based, precision medicine to prevent Alzheimer’s disease. Recent work by Dr. Richard Isaacson and an international team of clinicians and scientists showed that longitudinal, personalized risk management was feasible and effective for reducing cognitive decline and markers of AD risk. Many individuals may lower their risk factors yet are still stricken with dementia. But prevention, even slowing disease progression for one year, is becoming increasingly important as the development of diseasemodifying interventions becomes a reality.
It is helpful to understand a few key concepts related to disease pathophysiology to understand prevention and intervention. Plaques and tangles, clumps of the misfolded proteins betaamyloid and tau, are hallmarks of the disease. These clumps form when the proteins used in healthy brain cells for growth and stabilization break down to form toxic, sticky masses. We know that cardiovascular disease risk factors contribute to the formation of plaques and tangles. High blood pressure and cholesterol increase the risk of AD, likely related to the fact that the lining of blood vessels (vascular endothelium) is a significant source of betaamyloid. We also know that untreated, elevated blood sugar, or diabetes, is an additional risk factor. Accumulation of beta-amyloid plaques can interfere with insulin-related neuron growth, synapse formation and neurotransmitter production, among other things. Beta-amyloid also interferes with the function of the neuronal powerhouse (mitochondria) and ionic homeostasis, which is vital for cell signaling. Homeostasis is from the Greek words for the “same” and “steady” and refers to any process that living things use to actively maintain stable conditions for survival. Finally, beta-amyloid can trigger an immune response. The immune system can attack plaques as dangerous foreign invaders, resulting in neuroinflammation and proinflammatory cytokines. These chemicals increase inflammatory reactions resulting in a cycle of cell death. It is not always clear which came first, the chicken or the egg (the beta-amyloid or the cellular distress), but prevention and intervention targeting protein, vascular, blood sugar, energy and immune processes are promising.
Clearance of beta-amyloid has received significant research attention with mixed results, and a new drug from the pharmaceutical company Biogen is being reviewed by the FDA now. There are also compounds under examination that prevent the accumulation of toxic tau proteins, which form tangles associated with AD. Research on gene therapy, immunotherapy and nano therapy are also promising. Today, there are no available treatments for Alzheimer’s disease, but many interventions, such as drugs and vaccines, are on the horizon. These treatments result from the large volume of research and the growing number of research dollars from the National Institutes of Health, foundations and pharmaceutical companies dedicated to curing Alzheimer’s disease. There is a light at the end of the tunnel, possibly within the next three to five years.
This shrinking timeline for effective treatment for Alzheimer’s highlights the importance of preventing and preserving brain function. There are several strategies to address modifiable risk factors. For example, there is evidence that increased belly size is associated with increased dementia risk. Eating a heart-healthy diet like the Mediterranean diet can decrease belly fat and blood pressure, cholesterol and blood sugar. Exercise can protect and even create new energy-producing mitochondria in muscle and brain cells. There is evidence that age-related muscle wasting is associated with an increased risk of dementia. There also appears to be a link between sleep and dementia, with less than five hours of sleep per night and sleep apnea conferring increased dementia risk. Sleep apnea, or interrupted breathing during sleep, is often associated with snoring (see https://www.stopbang.ca/osa/screening.php for a simple screening tool) and is easily treated. Reducing chronic inflammation is important and is associated with maintaining oral health and seeing the dentist regularly. Systemic inflammation can be monitored based on blood levels of homocysteine, an amino acid involved in the production of proteins. Elevated homocysteine is linked to dementia and vascular damage. Some medications or combinations of medications can mimic memory loss, such as sleep aids and anxiety medication. It is important to talk with your doctor before making medication or significant lifestyle changes. If you are interested in learning more about longevity and optimizing health, Dr. Peter Attia has a well-respected and highly recommended podcast at peterattiamd.com.
However, not all interventions are effective for all individuals, which is why the concept of precision medicine in the prevention of dementia is becoming increasingly important. There is growing interest in developing a screening test panel for those without symptoms. It is important to “know your numbers,” including blood sugar, blood pressure, cholesterol, body fat and muscle mass, vitamin D and B12 levels, all of which are responsive to intervention. In addition, the genetic test for APOE4 mutation is becoming more accessible (23andMe). The APOE protein (apolipoprotein E) is associated with cholesterol metabolism, and mutations to the APOE gene are more common in people with dementia. If you have the APOE 4 mutation, healthy lifestyle is important, and dental cleaning has been recommended every three months. Tests for blood levels of beta-amyloid are commercially available, with tests for phospho-Tau not far behind. The blood test for homocysteine, a marker of systemic inflammation, is widely available.
For more information about prevention, a good place to start is the prevention module of the Alzheimer’s Universe website at AlzU.org. For questions about local resources and research opportunities, please get in touch with The Bridge, a new collaboration between the LSU Health Shreveport Center for Brain Health and the Alzheimer’s and Dementia Resource Center at (318) 656-4800. The Bridge is located at 851 Olive St. in Shreveport. Additional resources can be found at www.lsuhs.edu/cbh and alzbridge.org.
Contributions by Elizabeth Disbrow, PhD, director of the Center for Brain Health, professor of neurology, LSU Health Shreveport; Tyler Reekes, research associate, Center for Brain Health, LSU Health Shreveport; and Nathan Glassy, research associate, Center for Brain Health, LSU Health Shreveport.