By Math P. Cuajungco
The news is all too familiar – another Alzheimer’s disease drug trial bites the dust.
In the past several years, major pharmaceutical and biotechnology companies have announced failure after failure of their lead-candidate drug to halt the cognitive decline associated with Alzheimer’s disease patients initially diagnosed with mild cognitive impairment.
The impetus to treat sufferers at the early stages of the disease came about from lessons learned from similar failures where drugs were given to late-stage patients. Researchers argued that the compounds might have been ineffective due to the fact the disease is already past the point of no return and reasoned that perhaps giving it to patients with mild symptoms early on could stop the disease process.
As we know now, this is not the case.
There is also a faction that advocates testing drug leads to at-risk populations even before diagnosis, to find out if candidate compounds will be effective. Although this nip-it-in-the-bud approach makes sense, the target population would be those individuals with a family history of Alzheimer’s disease, suggesting a genetic or hereditary connection.
On the other hand, a good number of people who have no such family history but are likely susceptible to the disease due to environmental or lifestyle factors would be left out with this pre-diagnosis treatment – known in the medical field as prophylaxis. Whether this approach will work is yet to be determined. Despite these setbacks, scientists are still hopeful that an effective drug to treat the disease will be a blockbuster, because a long line of drugs is in the pipeline for clinical trials.
Reducing the risk for Alzheimer’s disease
One might wonder whether effective drugs against Alzheimer’s disease will ever become available. Until then, what can we do to reduce our risk from the ravages of the disease? How can we “SHIELD” ourselves? Recently, Rudy Tanzi and Deepak Chopra published a book that focuses on this premise. SHIELD is an acronym coined by Tanzi that stands for Sleep at least eight hours, Handle stress, Interact with others, Exercise, Learn new things and eat a healthy Diet.
Sleep: About eight years ago, it was reported that sleep helps clear beta-amyloid (see accompanying story) in the brains of mice. A similar study in humans showed that poor sleep is strongly associated with dementia, though it is not clear whether one leads to the other or vice versa. One thing is certain: Sleeping at least eight hours a day is very important. One strategy is to avoid looking at your electronic device at night because it emits blue light that could disrupt your sleep-wake cycle. Some individuals take up yoga or physical exercise, which not only provides cardiovascular benefits but results in a good night’s sleep. Lastly, making your bedroom dark with no detectable light helps some people sleep well.
Handle stress: Cortisol is a hormone released by the adrenal glands in response to stress, in what’s known as our fight-or-flight response. Let’s say you encounter a bear in the woods. Your reaction is to flee or confront the animal. Regardless of the choice you make, the end-point is survival, which makes the effect of acute stress beneficial to you. Long-term or chronic stress, on the other hand, is harmful due to the fact that cortisol has negative effects on learning and memory, as well as the immune system. Even in a fast-paced living situation, there are many ways to de-stress: meditate, take up a hobby, go to a yoga class or exercise.
Interact with others: Social interaction has many benefits and has been associated with positive mental health. Studies show that elderly people who are socially engaged, frequently involved in social activities and physically active have better cognition. There is no doubt that spending time with loved ones or friends strengthens relationships and provides many opportunities for an active lifestyle – a way to relieve or minimize the effects of stress.
Exercise: A study in rats showed that aerobic exercise such as jogging leads to the birth and growth of new brain cells in the hippocampus, the part of the brain involved in learning and memory. Individuals who regularly exercise also have better cardiovascular health than those who live a sedentary lifestyle. The relationship between cardiovascular health and normal brain function is clear: People who have high blood pressure are more likely to suffer from heart attack, stroke and dementia.
Learn new things: Studies have shown that individuals who speak a language other than their native language tend to show less cognitive decline as they age than those who speak only one language. This does not mean we should all take language classes to stave off Alzheimer’s. Learning new skills has also been associated with good mental health — for example, learning to play a musical instrument. The current trend is that we should engage in activities that challenge our mind and improve a type of memory such as solving puzzles, painting or coloring, and playing video games. One advantage of taking a class to learn a new skill is the social interaction.
Diet: Researchers agree the Mediterranean diet could be the key to minimizing the negative effects of aging in our brain function. The diet consists of eating fruits, vegetables, legumes, whole grains and nuts regularly, as well as a few servings of fish and poultry each week. Having moderate intake of red wine, which has been linked to good cardiovascular health, and spending your meals with family or friends make the experience more enjoyable.
You have probably noticed overlapping activities between categories. For example, eating a healthy diet with friends accomplishes two of the suggested categories of SHIELD. Taking up a new skill or hobby that may involve regular physical and mental activity, as well as social interaction, could also provide stress relief, exercise and quality sleep. Ultimately, the key to SHIELD-ing yourself against Alzheimer’s might be to select activities in which you will achieve all the physical, mental and social benefits at once and stick to them.
What happens during Alzheimer’s disease
The disease is diagnosed only after the patient has died and the brain tissue is collected and examined. The telltale signs of the disease are clumps of protein fragments known as beta-amyloid plaques found outside the brain cells and fibrous tangles of a protein called tau found inside the cells.
Beta-amyloid is a peptide fragment of a longer protein called amyloid precursor protein. There are two ways the amyloid precursor protein is cut in cells – one path leads to the production of beta-amyloid and the other to an innocuous peptide fragment called p3. It is the route of beta-amyloid formation through a protein cutter called BACE1 that’s a basis for efforts in drug development to prevent beta-amyloid plaques forming in the brain. Indeed, a recent study in mice engineered to develop beta-amyloid plaques but also devoid of BACE1 showed that disrupting BACE1 is a promising approach to rid the brain of plaques.
Whether this line of therapy would work for humans remains to be seen. Note, however, that a major pharmaceutical company last year pulled the plug for its clinical trial to prevent BACE1 from cutting APP. In the previous year, another trial targeting BACE1 was halted by another company due to its toxic side effect in the liver.
Another hallmark of Alzheimer’s is the tau protein tangles in brain cells. The protein tangles occur in brain cells of Alzheimer’s patients when tau becomes over-burdened by too many phosphate molecules attached to it, which is referred to as hyper-phosphorylation. It is not clear at what stage of the disease these tau tangles form, but scientists know they are associated with the severity of dementia.
The tangles seemingly begin in the areas of the brain involved in learning and memory, called the hippocampus, but spread into other brain regions as the disease progresses. A recent study suggests beta-amyloid as a key mediator for the diffusion of tau to other parts of the brain, which then become tangles inside the cells.
This concept is nothing new, because it is known that a protein called prion does spread in the brain and behaves as infectious particles when it is misfolded. Prions are well-known for their effect on cows (mad-cow disease), sheep (scrapie) and humans (Creutzfeldt-Jakob disease). There have been reports that beta-amyloid itself confers a prion-like effect when taken from a diseased brain and injected into a normal brain, which becomes diseased as well.
Additional studies are needed to verify the influence of beta-amyloid on tau’s prion-like property.
Although the failed clinical trials of drugs aimed at beta-amyloid plaques have fueled greater interest in pursuing tau tangles against Alzheimer’s disease, clinical trials directed at tau have not had much success either.
Math P. Cuajungco is a professor of biological science at Cal State Fullerton.
