What’s Next? Moving Forward with Alzheimer’s Research

Alzheimer’s disease is a neurodegenerative disease that causes dementia – a progressive set of symptoms that include loss of memory and cognitive abilities, such as problem solving and language, due to degeneration and death of neurons in the brain. Last year, there were 48 million people around the world living with Alzheimer’s disease. Not only is it physically and mentally harrowing for both the patient and their family members, it also places a huge strain on the healthcare system. As of yet, there is no cure for this fatal disease. However, ongoing research has resulted in some promising recent developments. New antibodies to target the main cause of neuron loss, new methods of drug delivery, and new methods of early detection are all being discovered. While not all of these discoveries will lead to promising cures, it is likely that some will allow Alzheimer’s patients to live better and cope with the symptoms.

While the disease is not yet fully understood, there are a number of hypotheses that have been used to research potential treatments. Currently, the main hypothesis for the cause of Alzheimer’s is linked to a build-up of two types of proteins in the brain. Firstly, the amyloid precursor protein (APP) – a long protein made up of hundreds of amino acids – which, when broken by two enzymes into a 42-amino-acid long chain, becomes beta-amyloid proteins. These proteins are sticky and build up into ‘plaques‘ between neurons, causing damage. Secondly, the protein tau—which normally helps maintain the cell transport system where molecules are transported—can misfold into twisted protein strands, or ‘tangles‘, of tau. These tangles form inside neurons, causing a loss of connection between neurons and eventually leading to loss of brain tissue. These two protein abnormalities are the most common and recognisable characteristics of Alzheimer’s within the brain, and are currently believed to be the main cause for neurodegeneration. However, other brain symptoms are present and how they affect the disease’s formation and progression is still unclear. Furthermore, a number of recent failed clinical trials of drugs targeted at beta-amyloid plaques have cast doubt on the accuracy of the amyloid hypothesis. Research in this area has been active for many years, but incomplete information about the disease has been a major obstacle. Firstly, not all patients display the same pathology and symptoms, making a reliable cure extremely difficult to find. The factors behind Alzheimer’s and their relationships and mechanisms are not fully understood. Furthermore, treatments that enter clinical trials have had limited effect; in the clinical trials between 2000 and 2012, only one compound was approved for for use, corresponding to a failure rate of about 99%.

Currently, there are two categories of drugs that delay the disease’s progression: cholinesterase inhibitors, which are used to treat mild to moderate cases; and memantine, which is usually recommended for as an alternative to cholinesterase inhibitors and for those with more severe Alzheimer’s. Cholinesterase, which is short for Acetylcholinesterase (AchE), is the enzyme that breaks down the neurotransmitter acetylcholine (Ach). One of acetylcholine’s functions is to form a pathway in the forebrain from the basal forebrain to the neocortex; degeneration of the pathway is linked to Alzheimer’s. As such, cholinesterase inhibitors reduce the enzymatic breakdown of acetylcholine, enhancing neurotransmission and hence maintaining brain function. Memantine is another medication option. It is an N-methyl-d-aspartate (NMDA) receptor antagonist – this means that the medication blocks these receptors from long-term activation as they cause neurotoxicity, ultimately damaging brain function. Yet for patients with Alzheimer’s, these drugs merely delay the inevitable. Researchers have therefore been trying to tackle the problem from new angles. Because damage to the brain is spread over a number of areas in Alzheimer’s pathology, researchers have developed various approaches to targeting the causes and symptoms.

Continuing the Search: Anti-Amyloids

Some researchers continue to focus on developing new anti-amyloids. One key area of investigation is immunisation compounds for Alzheimer’s, such as the antibody crenezumab (developed by Swiss companies AC Immune and Genentech). Crenezumab binds misfolded beta-amyloid proteins to prevent and remove plaque formations. Recently, although clinical trial results published in 2015 failed to meet their goals, later data analysis found that crenezumab had significant effects on a group of patients with a milder form of Alzheimer’s – in this group, the drug reduced cognitive decline by 35.4% and global function decline by 19.6%. These effects were found to be consistent and without limiting side effects, meaning that higher doses are possible to boost the effects in future trials. The companies have begun large-scale Stage 3 trials across the globe, where the antibody is being tested on diagnosed Alzheimer’s patients, particularly early-stage subjects.

However, this antibody follows in the footsteps of a number of failed predecessors, such as bapinezumab, which failed its late-stage trials in 2012, and many are wary of crenezumab’s chances for success. One previously studied antibody, aducanumab by Biogen, caused vasogenic edema – a dangerous swelling around the blood-brain barrier that causes leakage of fluid into the brain – in over half of Biogen’s own Phase 3 test subjects. While none of the cases caused long-term damage, this remains a risk for the antibody as it moves into larger-scale trials around the world. As this response—which may have been an immune response triggered by the injection of the antibodies—appeared mainly in those who carried a genetic predisposition for Alzheimer’s, it remains to be seen whether it will occur with crenezumab. As of today, the drug seems to be highly beneficial for those with very early stages of Alzheimer’s, but it’s unclear whether this is sufficient for it to be approved and eventually become available for the general public.

Drug delivery: crossing the blood-brain barrier

There is still widespread support for the amyloid hypothesis, but a string of failed clinical trials has led some researchers to believe that the answer lies elsewhere. Rather than treating the amyloids, some think that drug delivery is the key. One of the major obstacles to Alzheimer’s treatments is the blood-brain barrier: a layer of cells that protect the brain by preventing most molecules (including drugs targeted at the brain) from passing through blood vessels to the brain. The barrier hugely reduces the efficacy of many drugs and renders others unusable. However, scientists at Cornell University have recently discovered a way to briefly open the blood-brain barrier, allowing drug molecules to pass through. An existing heart-imaging drug, Lexiscan, activates adenosine receptors on the cells which make up the blood-brain barrier. These receptors then reduce the function of P-glycoprotein, the molecule that blocks entry to the brain. By using Lexiscan and then delivering chemotheraphy drugs to mouse brains, and an artificial human blood-brain barrier, the researchers found that the decrease in P-glycoprotein coincided with a marked increase of drug accumulation in the brain. While this has yet to be tested on humans, the study serves as proof concept that the blood-brain barrier can indeed be bypassed using Lexiscan.

Lexiscan is therefore extremely promising for future Alzheimer’s treatments. Not only can future antibodies—normally too large to cross the blood-brain barrier—be delivered directly to the brain, but the efficacy of existing drugs, cholinesterase inhibitors, and memantine could be significantly boosted. Newly developed antibodies, such as crenezumab, could also be delivered using this method – incorporating it into clinical trials could speed up the search for a viable cure by years. Furthermore, since Lexiscan is already a government-approved drug available on the market, the timeframe for making it widely available will be much shorter than that of newly developed compounds. However, the blood-brain barrier is also the brain’s defence against pathogens that could cause serious damage to the central nervous system if they were to pass through. These risks can be modulated by stringent medical screenings before the use of Lexicscan on a patient, but any disruption to normal brain function is inherently risky. The risks of cerebral edema may also be a potential factor due to an increase of liquid volume around the brain. Considering these significant risks, it remains to be seen whether this method will be safe to be tested and eventually used on humans.

Early detection or harm reduction?

While these discoveries may prove beneficial, the data from many clinical trials suggests that early detection trumps a well-developed treatment. The earlier treatment is administered, the better the chances of delaying Alzheimer’s with most of the new drugs. It is clear that early detection technologies need to be further developed – given that the hippocampus and the locus coeruleus have been found to be the earliest areas that display Alzheimer’s pathology—sometimes in early adulthood, decades prior to a diagnosis—there should be further study into how the disease forms. One of the issues with the clinical trial process itself is that it usually takes over a decade from the discovery of a new drug to widespread availability. Furthermore, many “failed” trials are setbacks for researchers as they impact funding, despite significant discoveries being made during the trial process. Additionally, drugs cannot be approved as cures unless their clinical trials meet targets in statistically significant numbers. Researchers, particularly pharmaceutical companies, may be overly optimistic in their goals for the new drugs they discover. By targeting harm reduction rather than disease modification, they may be able to have a more immediate impact.

Yet symptom-targeted drugs already exist, and pharmaceutical companies are looking for a profitable cure. This conflict of interest is one of the barriers to getting more drugs approved for the market. Another problem is with the clinical trials themselves: currently new drugs are only being tested on diagnosed Alzheimer’s patients who sign up for studies. Tau pathology can in fact be detected in the locus coeruleus as early as early adulthood, but it does not always become full Alzheimer’s. More preventative studies should therefore be carried out with the new prevention drugs. One ongoing clinical trial is the A4 study (Anti-Amyloid Treatment in Asymptomatic Alzheimer’s disease), in which solanezumab (an anti-amyloid antibody developed by Eli Lilly, structurally similar to crenezumab) is being tested on participants with normal cognition who may be at risk for developing Alzheimer’s (based on PET scans showing amyloid deposits in the brain). Crenezumab is also being tested as a preventive measure for an extended family who all carry a genetic trait which causes early-onset Alzheimer’s. By increasing testing on early-stage patients, clinical trial results will certainly be more significant, allowing drugs to reach the market more quickly.

Given the importance of early treatment, wider clinical trials on individuals before they are diagnosed with full Alzheimer’s may be the key. Furthermore, combination therapy has not yet been investigated as another possibility. A study combining a vaccination of an antibody with some of the existing cholinesterase inhibitors could prove very enlightening. Testing these new discoveries together may boost efficacy by treating the pathology in a multidimensional way.

It’s time to test drug compatibility to give Alzheimer’s patients a better chance to live longer, healthier lives. There is a long road to finding a cure, but promising multidimensional approaches to detection and treatment are signs that we are gradually moving closer.

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