On Target - New Focuses for a Potential Alzheimer’s Cure

by Women's Brain Health Initiative:Over the last three decades, scientists have focused primarily on two targets to eradicate Alzheimer’s disease (AD) - amyloid and tau. “Alzheimer’s is characterized by deposits of amyloid – essentially the grouping of abnormal proteins that cause cells to degenerate – and this debris forms plaques in the brain,” which can be observed in positron emission tomography (PET) scans, says Dr. Yves Joanette, Scientific Director of the Canadian Institutes of Health Research (CIHR) Institute of Aging, and former chair and current member of the World Dementia Council – an international charity working to defeat dementia.“The thing about amyloid deposits, though,” Dr. Joanette continued, “is that they aren’t only found in the brains of people with Alzheimer’s.” There are many documented cases of individuals who did not demonstrate any signs or symptoms commonly associated with AD, but whose brains contained significant amounts of amyloid plaques. Nevertheless, scientific understanding is that amyloid is not good for the brain, irrespective of whether or not the person is suffering from AD.In addition to amyloid, the Alzheimer’s brain concurrently experiences “accumulation within brain cells of neurofibrillary tangles,” explains Dr. Joanette, which is a distortion of the normal tau protein in the brain.“The most important discovery over the last decade is that these amyloid and tau tangle phenomena are occurring well before any clinical signs of Alzheimer’s, sometimes upwards of 25 to 30 years before.”The challenge, therefore, is to attack the abnormal build up of plaques and tangles early enough to prevent this mind-robbing disease from taking hold.To date, much of the effort to prevent, slow, or reverse AD has focused on finding one drug that would eliminate the accumulation of amyloid and tau. “The area of dementia, for the pharmaceutical companies, has been the biggest nightmare in terms of negative results,” says Dr. Joanette. While some possible drug options have shown promise in removing amyloid and tau deposits in animal studies, these treatments have failed in the critical “phase 3” human clinical trials. So far, experimental AD drugs have had a dismal track record, with more than 100 failures. Consequently, a one-size-fits-all solution to eliminate amyloid and tau build up may be too simplistic a target to find a cure for AD and other dementias.In other diseases such as HIV, for instance, there are three to four drugs, well-balanced to each individual, that have been found to appropriately manage the disease, Dr. Joanette observes. And HIV is a single, simple virus, whereas AD and other diseases that cause dementia are now understood to be much more complex disease processes than initially thought, and therefore it makes sense that such diseases would also require multi-pronged approaches.In fact, Dr. Howard Chertkow, the Scientific Director of the Canadian Consortium on Neurodegeneration and Aging (CCNA) and Senior Scientist at Baycrest’s Rotman Research Institute in Toronto, says that we still do not even know what causes AD in the first place.The difficulty in finding a treatment for AD arises, in part, from the lack of knowledge of the origin of the disease.There has been nearly two decades of anti-amyloid therapy without convincing evidence of slowing Alzheimer’s progression, says Dr. Chertkow. Amyloid and tau might be the result of having AD, rather than the initial cause, posits Dr. Joanette, which has propelled some researchers to query what causes the first changes in the brain that then leads to amyloid and tau tangles. Where amyloid and tau are concerned, there are still a few trials awaiting results. Dr. Chertkow warns, however, that if these clinical trials are not successful, then many members of the research community will likely declare the amyloid theory “if not dead, then at least on its deathbed.”In order to make a breakthrough in understanding and treating AD, scientists across the country and around the globe are beginning to look for “other approaches, other considerations, other things that might explain Alzheimer’s disease,” says Dr. Chertkow. The following is an overview of some of the latest trajectories of research.“Just because something goes along with the disease (i.e. amyloid and tau), it doesn’t prove that it causes it. association is not causation.”Oxidative Stress and Free RadicalsThere is mounting evidence that free radical-induced oxidative damage may play a role in the pathogenesis of AD. Free radicals are created by unstable oxygen species in the brain, which in turn may attack and damage lipids, proteins, and DNA.Dr. Hyman Schipper, a Professor of Neurology and Medicine (Geriatrics) at McGill University in Montreal, has discovered an enzyme in the bloodstream that is related to oxidative stress – heme oxygenase-1 suppressor – that is nearly strong enough to be a diagnostic test for AD. There may be a genetic component to the free radical hypothesis since individuals who have the main risk gene associated with AD – Apolipoprotein E (APOE-4) – have been found “to be less protected from free radicals.”Those who have experienced head trauma, which is a known associated risk for AD also have more free radical damage, says Dr. Chertkow. Anti-oxidant therapy may be an approach to halt free radical damage, but more research is required to better understand this treatment option.Although free radical damage may be a consequence of normal aging, researchers are investigating how it might affect abnormal aging processes that occur in AD as well.Chronic InflammationTargeting specific elements of the inflammatory process could be useful in treating or preventing AD. Some researchers believe that there may be a “trigger that initiates the cascade of events that eventually causes neurodegenerative processes, which then causes amyloid deposits,” observes Dr. Joanette.“If you look at the plaques of Alzheimer’s disease in the brain, you see inflammatory cells,” says Dr. Chertkow. These cells could be a response to “some inflammatory agent we don’t yet recognize, such as a virus or a fungus.”Researchers at McGill University are examining PET scans to observe the life cycle of inflammation in the brain.“It may not be a simple one-way story,” says Dr. Chertkow. It could be that only some AD patients are highly affected by inflammation.University of British Columbia’s neuroscientist Dr. Patrick McGeer has suggested that a simple anti-inflammatory drug like Advil could work for AD, but there has been no research on this to date because the long-term use of ibuprofen can increase one’s risk of other health problems, such as gastrointestinal issues.Early on, inflammation appears to be a “protective” mechanism, but later becomes harmful.Glucose MetabolismPET scans of individuals with AD have shown that their brains do not absorb glucose in the same manner as healthy brains. In type 1 or 2 diabetes, not enough insulin (or no insulin) is produced to process glucose correctly or the body no longer responds to insulin, which affects the functioning of the entire body. In AD, it appears that a similar problem is occurring, but instead of causing problems in the body's functioning, the effects occur in the brain.There are currently trials underway in which researchers are administering intra-nasal insulin to participants in order to examine its effects on glucose activity, as well as research exploring the ways in which bypassing glucose altogether (for instance, through aketogenic diet) might impact AD.Indeed, so close is the link between AD and diabetes that scientists have often referred to the disease as “Type 3 Diabetes.”CaspasesDr. Andréa LeBlanc, a Professor of Neurology and Neurosurgery at McGill University and a researcher at the Bloomfield Center for Research in Aging in the Lady Davis Institute for Medical Research in Montreal, has been examining how changes in the levels of the caspases enzymes – those enzymes that play an essential role in regulating cell death – might be related to AD.Dr. LeBlanc’s research team detected changes in caspases levels very early on in individuals with AD, indicating that caspases may not only contribute to neurodegeneration, but also may promote the underlying pathology associated with the disease. Therefore, caspase inhibitors may prove to be an effective strategy for treating AD. Amyloid-Precursor ProteinThe amyloid precursor protein (APP) has been investigated in connection with its role in AD due to its cleavage resulting in the production of the amyloid-beta protein that aggregates into the plaques characteristic of the disease. Clinical trials are underway to determine whether removing APP will cease amyloid production.The problem, though, is that APP is thought to play a key role in neural growth and repair. One theory is that the fatty/lipid surface of the cells that this protein interacts with could be compromised in some way (interestingly, APOE-4 is involved in carrying fats/lipids). Omega fatty acids are therefore being considered in new research, as well as medications that could excise lipids that are “too thick” (i.e. those that would then go on to form amyloid deposits). Vascular FactorsRecently, there has been keen interest in vascular factors that may increase the risk of developing AD. Diabetes, a high level of cholesterol, and tobacco smoking, for instance, have each been associated with a higher risk of AD.“There is clearly a strong interplay between vascular and brain health,” says Dr. Chertkow. “Vascular changes are happening earlier and more frequently than we realize – not only when an individual has suffered a stroke, but even without clear events in individuals with diabetes, hypertension, and other vascular risk factors.” Accordingly, controlling vascular factors may be an important mechanism for the prevention of AD.The treatment of one of the important atherosclerotic vascular risk factors, hypertension, has been shown to reduce the risk of dementia, including AD or vascular and mixed dementias.Cognitive Reserve“If you look at the brains of people with Alzheimer’s, it is now becoming clear that you don’t just see amyloid, you see multiple forms of pathology, multiple abnormalities,” says Dr. Chertkow. “There are dozens of combinations of pathologies. Maybe what we call Alzheimer’s is a final common pathway for diseases that affect the cortical cells.”Defeating AD could be less about finding solutions to “this protein or that protein,” says Dr. Chertkow, and more about focusing on strengthening what is referred to as “cognitive reserve,” which describes the mind’s resilience to damage of the brain.Rather, certain life experiences determine someone’s cognitive reserve and, therefore, his or her ability to avoid dementia or memory loss. In this way, some people have better cognitive reserve than others, and are better at withstanding the effects of certain pathological proteins as they age.Several studies have indicated that engaging in activities that stimulate cognition (such as learning a new language, completing crosswords, and having high levels of social interaction), as well as exercising regularly, can help improve one’s cognitive reserve and thereby reduce the risk of developing dementia. Dr. David Bennett, the Director of the Rush Alzheimer’s Disease Center in Chicago, is currently investigating the molecular basis of cognitive reserve in order to produce a drug that would boost it.Research has suggested that the extent of someone’s cognitive decline does not correspond with the amount of biological damage in his or her brain as it ages.GeroScienceWhile we all know it, we often forgot that the main risk factor for AD and other forms of dementia is age, says Dr. Joanette. Researchers are therefore examining “the relationship between the biology of aging itself and what’s going on to trigger neurodegenerative diseases and other chronic diseases.”Perhaps the biology of aging is interacting with other bodily systems and issues such as late-life diabetes or arthritis. More research is being conducted on these types of questions in a new area of research referred to as “GeroScience.” Just last year, CIHR launched a call to support grants for researchers in this nascent field of study.Gut MicrobiomeThe human body is host to trillions of microbes. In fact, slightly more than half of the cells found in our bodies are microbes – mostly bacteria, but also fungi, viruses, protozoa, archaea, and other microorganisms. The majority of these microbes reside in the gastrointestinal (GI) tract – commonly referred to as the “gut” – and the rest can be found in different parts of the body, including on the skin, in the urogenital tract, and in the nasal, oral, and otic (ear) cavities.Microbes handle a variety of essential and beneficial functions in the human body. They play a fundamental role in digestion, nerve cell growth and survival, immunity, and inflammation.As such, researchers are now exploring the role of gut bacteria in the development and treatment of AD. The Wisconsin Alzheimer’s Disease Research Center, for instance, found that individuals with AD have different gut microbiome compositions than those without the disease. It is an emerging area of research that might yield novel treatments for AD in the future – including using probiotics as a preventative measure and fecal transplants for those already afflicted with the disease.Evidence is emerging that suggests that microbes affect cognition, behaviour, and mental health, particularly through interactions between the gut microbes and the central nervous system, commonly referred to as the “gut-brain axis.”Porphyromonas GingivalisAccording to new research published in Science Advances in January 2019, there may be a relationship between a common bacterium known as Porphyromonas gingivalis (Pg) – which is found in our mouths and causes gum disease – and the development of AD. In addition to Pg itself, the research team detected the organism’s toxic proteases (referred to as “gingipains”) in the neurons of patients with AD.The researchers posit that targeting gingipains may reduce neurodegeneration in AD. Human clinical studies are about to commence with small-molecule gingipain inhibitors that were found to protect neouronal cells against Pg in the animal studies.Each of the new areas of research might in fact be part of the “initial triggering of the cascade of events that eventually turns into a neurodegenerative process, which then turns into the amyloid and tau changes,” says Dr. Joanette.Instead of a single drug, then, it is more likely that individuals with AD will be prescribed several medications at once, similar to the treatment of HIV. Moreover, a growing body of evidence suggests that interventions will not just involve pharmacological solutions, but also behavioural modifications, such as changing one’s diet and sleep habits, and engaging in physical exercise.It also means that collaboration between researchers, academia, and industry is more important now than ever. This is part of the reason why the Canadian Consortium on Neurodegeneration and Aging (CCNA) was created, which is a significant investment on the part of the Canadian government, and industry organizations like Women’s Brain Health Initiative and the Alzheimer’s Society. The consortium encourages data pooling, as well as national and international collaboration.“I strongly believe that no country, no sector alone will crack the code – we need to work together here,” says Dr. Joanette. Canadian researchers are already sharing data with U.S. and European collaborators in over 30 countries. “We should be more optimistic now than we were five years ago,” says Dr. Joanette, “when the approach was same-old, same-old, and probably naïve in its search for a single solution.”Importantly, researchers are now more aware that given the complexities of AD, conquering the disease will involve multi-pronged interventions.Source: MIND OVER MATTER V8