The current opioid epidemic involves hundreds of thousands of individuals who have become addicted to opioids such as extended-release oxycontin. It should be remembered, however, that opioids are not just addictive recreational drugs. They also have an important bona fide use in medicine. Opioids are the most effective drugs we know of for the treatment of many kinds of pain, and normal surgeries—as practiced today in hospitals around the world—would be impossible without their use. Opioids are effective in controlling many types of pain. However, their chronic use almost inevitably leads to addiction. An important goal therefore is to produce drugs that effectively control long-term pain, but are free from the addictive potential of opioids. Since the advent of the opioid crisis, the National Institutes of Health (NIH), which is the main funding source for medical research in the United States, has been offering more research grants for people who are trying to develop “non-addictive”, but highly effective, analgesic drugs. One of the reasons why drugs like morphine are so good at controlling pain, and also why they have so many side effects, is that their receptors, known as μ-opioid receptors, are abundantly expressed at diverse points throughout the nervous system. These receptors are localized in peripheral nerves that transmit pain sensations, in the spinal cord, and in higher brain centers where they effectively control the flow of information along pain-conducting nerve pathways. Whether the receptors for other potential analgesics will be so conveniently placed is not at all clear, and so reproducing the powerful and widespread analgesic effects of opioids using other approaches may be difficult. Cannabis is one possibility, as cannabinoid receptors—like those for opioids—are widely expressed in the nervous system. Other approaches to the problem, such as synthesizing novel opioids that are free of addictive potential, have also proven to be challenging and, in spite of numerous claims in the scientific literature, have never ultimately succeeded. For reasons such as these, the replacement of opioids as generally effective analgesic drugs is a challenging undertaking.

On the other hand, all types of pain have unique triggers. For example, the trigger for osteoarthritic pain, involving movement of a degenerating joint, is different from that of painful diabetic neuropathy, involving dying peripheral neurons, or other causes. It is quite possible, therefore, that rather than discovering a replacement for opioids per se, new drugs for pain will be developed in a disease-specific manner, based on the particular pain-triggering mechanism that is involved in each syndrome. One example of such an approach is a new drug that is targeted to the treatment of sickle cell disease (SCD).

To understand this new therapeutic approach, we should first look at the mechanisms that underlie SCD, which has a particularly interesting origin. One of the greatest scourges known to man is the mosquito. The bite of the mosquito is associated with the transmission of a large number of diseases including dengue, West Nile virus, chikungunya, yellow fever, filariasis and zika, among others. However, by far the most prevalent and devastating of mosquito-associated diseases is malaria, which has tracked the development and migration of human society over millions of years. As described in a recent book (The Mosquito by Timothy C. Winegard), mosquitoes accompanied humans as they left Africa and colonized many other parts of the world. For example, the conquistadors brought malaria with them when they first came to the New World and it was diseases of this type, rather than their prowess as warriors, which were probably mostly responsible for their relatively easy conquest of Central and South America. Mosquitoes tend to breed in warm, marshy areas such as the Pontine Marshes surrounding the city of Rome which, in ancient times, were notorious for being a hot bed of malaria. Here again, it is quite possible that it was these malarial marshlands that protected Rome from many rampaging invading armies over the years.

An Anopheles mosquito takes a blood meal

Prior to mosquitoes being identified as the “vector” that carried the disease, it was thought that malaria was spread by foul air—hence its name mal (bad)-aria (air). In actuality, malaria is spread by the bite of female Anopheles mosquitoes. The reason why female Anopheles mosquitoes bite you is to obtain your blood. Male and female Anopheles mosquitoes actually feed on nectar—blood isn’t what they eat. However, it turns out that there are nutrients in human blood—protein and iron—that are vital for the female Anopheles mosquito to be able to develop her eggs. This is the reason why she will drink about 3 millionths of a liter of human blood when she bites a human victim.

However, in addition to drinking your blood to obtain iron, mosquitoes also take up and inject disease-causing agents which basically go along for the ride. The infectious agent that causes malaria is a protozoan (single-celled eukaryotic organism), and we have a detailed description of its entire life cycle. There are actually several closely related protozoan parasites that can cause the disease. Moreover, there are also different species of mosquitoes that can spread malaria. However, only different types of female Anopheles mosquitoes can transmit human malaria. The organisms involved are 5 species of the protozoan Plasmodium—P. vivax, P. falciparum and P. malariae being the most common forms of the disease in humans. Related protozoa can infect other animals including birds and even fish. When a female mosquito bites somebody, if her victim is infected with a malaria parasite—let us assume it is P. falciparum as an example—then she will also take up male and female protozoan gametocytes (precursors of sperm and eggs) that circulate in the victim’s peripheral blood. Once within the mosquito, these gametocytes will develop further into male and female gametes (the sperm and eggs). The motile male gamete seeks out a female gamete and fertilization results in a motile zygote, also known as an “ookinete,” formed within the lumen of the mosquito’s gut. The ookinete then penetrates the gut wall where it becomes an “oocyst.” This then multiplies, forming infectious “sporozoites” that migrate to the salivary glands of a mosquito and are injected when the mosquito bites to obtain her next blood meal. Once the infectious sporozoites have entered the blood of the victim, they circulate around the body, eventually taking up residence in liver cells where they undergo further multiplication (exoerythrocytic schizogony), producing the next stage of development: the merozoites. Merozoites exit the liver into the blood and they are the species which now infect red blood cells (erythrocytes). Here, they multiply further to produce more merozoites which then destroy the erythrocyte and enter the blood once more and infect further erythrocytes. This process continues ad infinitum, until the host’s blood is used up and the individual dies. During the time when merozoites are multiplying within red blood cells, some of them turn into gametocytes that can be taken up by a mosquito during a blood meal to be transferred to the next victim. And so it goes. Around and around in a horrible dance of death and destruction reminiscent of the most terrifying scenes of the classic horror movie, Alien.

Life cycle of the malaria parasite

The well-known bouts of fever associated with human malaria result from rounds of bursting of red blood cells and release of infectious particles and toxins. The different types of Plasmodium parasites have slightly different properties in this regard generating “tertian” or “quartan” fevers which occur on average every two or three days. P. falciparum is the most deadly form of the disease. Some types of malaria such as P. vivax can also produce forms that lie dormant in the liver (hypnozoites) even when the disease has been cleared, only to awaken again after many weeks to initiate another deadly round of fevers, vomiting, and other symptoms of the disease.

The powerful selection pressures on individuals living with the constant threat of malaria in Sub-Saharan Africa led to the appearance of a genetic trait some 7,300 years ago that afforded some resistance to P. falciparum. This trait was caused by a mutation in the protein hemoglobin, the major protein found in red blood cells whose job is to carry oxygen from the lungs to the rest of the body. The most common mutation is known as sickle hemoglobin (HbS). HbS is a structural variant of normal adult hemoglobin. Adult hemoglobin (HbAA) is made up of two α and two β globin chains. HbS is the result of a single point mutation (Glu → Val) on the sixth codon of the β-globin gene. People who are heterozygous for the HbS allele carry the sickle cell trait (HbAS) but do not have SCD, whereas individuals who are homozygous for the HbS allele have SCD of which sickle cell anemia (SCA) is the most common manifestation. SCA is characterized by chronic hemolytic anemia, unpredictable episodes of pain, and widespread organ damage.

SCD is one of the most common genetic disorders found in the world. An estimated 20–25 million people live with homozygous SCD (HbSS). Approximately 300,000 infants are born annually with HbSS. Areas with a high prevalence of malaria such as Sub-Saharan Africa, the Mediterranean basin, Middle East, and India tend to have higher populations of patients affected with SCD. In the United States, approximately 100,000 people—many of them the descendants of the African slave trade—have SCD, accounting for more than 110,000 sickle cell-related hospitalizations annually. There is a wide variability in the clinical severity of SCA, as well as in the life expectancy. Interestingly, although people who carry the HbAS trait (heterozygotes) are clearly resistant to malaria, the mechanism of this effect isn’t entirely clear. Different kinds of biochemical changes have been detected in red blood cells from HbAS individuals, which must make it harder for P. falciparum to establish an infection but there is no real consensus as to how this occurs. Clearly, SCD is an extremely serious health problem. The fact that it has been maintained in populations such as those in Sub-Saharan Africa where malaria is endemic, speaks to the fact that just about anything is better than having malaria.

Individuals who are homozygous for hemoglobin S (HbSS), having two affected β-chains, develop SCD. The HbS allele has a lower-than-normal affinity for oxygen and also has a tendency to aggregate at low oxygen concentrations. Hence, when red blood cells have delivered their oxygen to the tissues and are returning to the lungs via the venous system in an oxygen-depleted state, the hemoglobin of SCD patients polymerizes, which produces sickle-shaped malfunctioning erythrocytes and reticulocytes (erythrocyte precursors). These cells are sticky and form clumps that occlude blood vessels, particularly small and some large vessels producing what is known as a vaso-occlusive crisis (VOC) which causes ischemic injuries. The sickled red blood cells are also brittle and burst, producing profound hemolytic anemia. During a VOC, the most common complaint is pain, and recurrent episodes may cause irreversible organ damage. One of the most severe forms is the acute chest syndrome which occurs as a result of infarction of the lung parenchyma. This can rapidly result in death. For a patient with SCD, both chronic pain and intense bouts of acute pain are particularly hard to deal with. Traditionally, patients with SCD-associated pain are treated with opioids and around a quarter of patients use opioids chronically throughout life, but of course, this also comes with the well-known risks of chronic opioid use.

In order to produce an alternative to opioid use, we need to know exactly why pain occurs in SCD. Nerves that sense pain innervate blood vessels and can be activated by inflammatory mediators and other processes occurring during a VOC. Drugs that interfere with these processes may be helpful in treating pain occurring in SCD patients in particular. Recently, there has been progress in achieving this aim. The first new therapy to be introduced for treating SCD was hydroxyurea (or hydroxycarbamide), which is the only drug frequently employed in SCD management that is approved by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Hydroxyurea’s principal mechanism of action is stimulating the production of HbF: a fetal form of Hb. When HbF is produced, it reduces HbS polymerization and so ameliorates pathological processes such as sickling, VOCs, and events downstream of these triggers. The mechanism by which hydroxyurea induces HbF generation is unclear. Since 1998, hydroxyurea has been the only FDA-approved therapy for SCD. By increasing both fetal hemoglobin concentrations in erythrocytes and reticulocytes, hydroxyurea treatment has significantly reduced the rates of VOCs, subsequent hospitalizations, and mortality in a range of patients. Unfortunately, despite these benefits, adherence to a hydroxyurea regimen has been problematic for some patients. Adverse effects of the drug include bone marrow suppression, large inter-patient variability in the effects it produces, and variations in the maximum tolerable dose. Consequently, other therapies have been sought based on a detailed understanding of the molecular and cellular events that produce VOCs.

Disturbances in blood flow produced by phenomena such as red cell sickling can be “sensed” by the endothelial cells that line blood vessels. Circulating sickled blood cells adhere to each other and to the activated endothelium, contributing to and potentially initiating VOCs. Activation of endothelial cells involves a large number of cellular responses that have pro-inflammatory consequences. For example, in postcapillary venules, activated endothelial cells express the proteins P‑selectin and E‑selectin. These are lectin-like molecules that can bind to specific patterns of sugar residues attached to proteins on the surfaces of circulating cells, allowing them to leave blood vessels and enter tissues as part of the inflammatory response. Activated platelets and adhesive sickle erythrocytes can adhere to circulating or endothelium-bound cells like neutrophils and form aggregates. Sickle erythrocytes can also bind directly to the activated endothelium. Endothelial cell activation—which occurs as a consequence of endothelium-derived nitric oxide (NO) depletion by cell-free hemoglobin released during hemolysis—oxidative stress, and constant inflammatory processes all play a key role in the initiation of VOCs. The adhesion of red blood cells and leukocytes to the activated endothelium acts as a trigger for VOCs.

These mechanisms means that P-selectin may well be an important drug target in situations like SCD. Over the past 25 years, selectins—particularly P-selectin—have been shown to contribute to pathological inflammation and thrombosis in many preclinical disease models, including atherosclerosis, ischemia–reperfusion injury, arterial thrombosis, and deep vein thrombosis. Patients with SCA develop injury to many organs that is consistent with repeated episodes of ischemia–reperfusion injury caused by the occlusion of blood vessels in VOC. Models of sickle cell anemia in experimental animals have established that sickled red cells obstructing small vessels trigger pathological inflammation and thrombosis that involves adhesive interactions among red cells, platelets, and the endothelium. P-selectin on the surface of activated platelets and endothelial cells binds directly to ligands on sickled red cells and immune cells like neutrophils. Blockade of P- or E-selectin decreases these adhesive interactions and improves microcirculatory flow in sickle cell mice. Results such as these suggest that agents that interfere with the functions of P-selectin might have value in preventing VOCs in SCD, and such an approach has recently been shown to have considerable promise.

Crizanlizumab is a recently developed humanized monoclonal antibody (a “mab”) that binds to P-selectin on the surface of endothelial cells and platelets and blocks its interaction with other cells. A large international clinical trial investigated the effects of crizanlizumab therapy on the rate of VOCs in a total of 198 participating SCD patients (aged 16–56 years), during 52 weeks of treatment. The intravenous administration of the P-selectin inhibitor was well tolerated, and high-dose crizanlizumab (5 mg/kg) was associated with a significantly lower frequency of VOCs in the treated patients, compared with the placebo group, where the median rate of VOCs per year was 1.63 versus 2.98 with placebo. Additionally, the median time to first crisis was significantly longer with 5 mg/kg crizanlizumab than with placebo (4.07 vs. 1.38 months). With VOCs being the major contributing factor to hospitalizations and reduced patient quality of life, these results were considered to be extremely promising and the United States Food and Drug Administration granted crizanlizumab a “Breakthrough Therapy” designation for the prevention of VOCs in SCD, implying that crizanlizumab demonstrated substantial improvement over existing therapies based on the available preliminary clinical evidence. On November 15, 2019, the FDA approved crizanlizumab-tmca (ADAKVEO, Novartis) for use in the reduction of the frequency of VOCs in adults and pediatric patients aged 16 years and older with sickle cell disease.

The FDA approval of crizanlizumab is hopefully good news for SCD sufferers. It also illustrates the important principle of treating pain on a disease-by-disease basis rather than going for a “home run” knockout drug that will treat more or less everything. This is what happened in the field of cancer. In the end, there was no “cure for cancer.” What we have achieved is a piecemeal approach where different cancers are targeted with different types of therapeutic agents depending on their particular mechanisms. There are plenty of painful diseases that might be helped by such an approach. Consider Ehlers-Danlos syndrome (EDS), for example. Like SCD, EDS is a genetically inherited disease which, in this instance, attacks connective tissue rather than the blood. Like those with SCD, EDS patients are afflicted with chronic pain that is often treated by long term use of opioids. However, judging by the success of crizanlizumab for SCD, we can easily imagine producing a drug for EDS pain that was directly targeted to a specific trigger. Moreover, there are many other painful diseases of this type. It is unlikely that we will ever improve on opioids for some types of pain but, as for many other situations, progress may well be made one step at a time.


Like many people, I often enjoy watching a good TV series in the evening. I really like crime shows and, of course, there are plenty of excellent ones. A case in point is the British TV series “Unforgotten.” Once I started to watch it, I was glued to the TV for the entire 3 series run. Each series revolves around the discovery of buried bones—for example under a freeway, in a river or in the basement of a house. But whose bones? As it turns out, they all belong to people who went missing several decades ago and nobody ever found out why. In other words, these are cases that have been forgotten. But Detective Chief Inspector Cassie Stuart and her sidekick, Detective Inspector Sunny Khan, want to set things right and figure out who these people were, what awful things might have happened to them and who was responsible. They want the cases to be “unforgotten” and the perpetrators of the crimes brought to justice.

As it turns out, the theme of forgetfulness not only concerns Cassie’s role as a detective but also her personal life. Cassie lives with her father who is getting on in years. Now he has started to forget things. But is this just normal forgetting or is something more serious involved? Perhaps this is the start of senile dementia? Cassie and her Dad argue about whether he should be tested or not. The Dad says he is fine—Cassie isn’t so sure. And, of course, this is a scene that is played out in many families all over the world. Dementia is a terrible fate, a long decline into a cognitive void where eventually everything is forgotten. But is “unforgetting” for these dementia victims a medical possibility? The recent announcement of the first treatment that might actually slow the cognitive decline in patients with Alzheimer’s disease has been hailed as a major breakthrough and has generated great excitement in the media.

It has been argued that the group of syndromes termed “senile dementias” are the most serious health problem afflicting the entire planet. Some 50 million people throughout the world suffer from dementias which affect the victim’s ability to remember things and to function effectively in everyday life. Paranoia and personality changes also often occur. Alzheimer’s disease (AD) is by far the most common form of dementia, making up some 70% of the victims. Other common dementias include Lewy body dementia, vascular dementia and frontotemporal dementia. Overall, the cost of treating AD throughout the world has been estimated at somewhere around a billion dollars (to be precise, in 2015 it was actually calculated as being $818 million). Unfortunately, although we now have a much better idea as to the natural history of the disease and its potential mechanisms, no disease-modifying interventions are available, only some medications that produce a small improvement in symptoms. This isn’t from want of trying. Until recently, most “Big Pharma” drug companies had very active discovery programs in this area. But with no effective new drugs on the horizon, they are beginning to lose heart and many of these programs have been discontinued. Of course, it’s a difficult problem. The disease is very long lasting, so it is hard to assess whether a potential therapy is really working or not without running sophisticated clinical trials over long periods of time—and, of course, these are extremely expensive. Hence, the announcement that something might actually be working is reason for considerable excitement for patients and researchers alike.

To understand what is going on, we need to take a look back at exactly what we know about the causes of AD. Naturally, there are reports of people becoming demented throughout history, particularly elderly people. However, the study of dementias as a part of modern medicine began on 25 November, 1901, when a 51-year-old woman named “Auguste D.” (actual name, Auguste Deter) was admitted to the Municipal Asylum for Lunatics and Epileptics in Frankfurt, Germany. The doctor who examined her was Alois Alzheimer. Among the things that Alzheimer noted was that the patient appeared extremely paranoid and deluded, imagining that her husband was having an affair with a neighbor. She also had difficulty remembering things and performing everyday tasks like cooking. Her condition worsened over time, and eventually, she was even unable to recall things that had only recently occurred. Auguste D. remained in the institution until her death in 1904.

Amyloid plaques and neurofibrillary tangles

Alzheimer, an expert neuropathologist, subsequently examined Auguste D.’s brain and described some striking abnormalities. These included the presence of the “neurofibrillary tangles” (NFT), “amyloid plaques,” and nerve degeneration which are now known to constitute the cardinal pathological hallmarks of the disease. Further patients suffering from similar symptoms with the same brain pathology were then recognized, and in 1910 the disease became officially known as Alzheimer’s disease. Originally, AD was defined as a disease in which young people inappropriately developed the cognitive problems associated with old age. However, it was eventually realized that the disease defined by its similar cognitive and pathological signs actually affected both young and old people alike. By the 1960s, it was becoming apparent that the brains of all patients with AD exhibited tangles and plaques. Interestingly, however, there were also examples of elderly people who possessed these pathological signs but were not demented, making the precise relationship between the observed neuropathology and dementia unclear. On the whole, however, the increased occurrence of plaques and tangles seemed to correlate with the seriousness of dementia. But were the protein constituents of tangles and plaques actually responsible for producing AD or were they just features otherwise associated with the course of the disease?

Clues as to what was going on came from the study of human genetics. It had been recognized as early as the 1930s that there were some families in which several people developed AD early in life with a pattern suggesting a Mendelian autosomal dominant form of inheritance. It was also observed that patients with Down’s syndrome, who have an extra copy of chromosome 21, always seemed to develop AD at some point in their lives. Around this time, a protein called the amyloid β-protein 1-42 (Aβ) was identified as being the major protein component that made up the core of the amyloid plaques found in AD brains. This small protein was found to be derived from the cleavage of a larger transmembrane protein, subsequently named the amyloid precursor protein (APP) which, interestingly enough, was found to localize to chromosome 21. Mutations in this gene were also linked to some cases of early onset AD. In other cases, mutations in the presenilin gene, located on chromosome 14, were linked to early onset AD. Presenilin was found to be part of an enzyme complex eventually named γ-secretase that was responsible for making one of the cuts that releases Aβ from APP. The second cut that released Aβ was found to be made by another enzyme named β-secretase. It is thought that this pattern of APP cleavage is ultimately pathogenic. Under other conditions, APP can be cleaved by an enzyme called α-secretase that precludes it being cut by β-secretase; this cleavage pattern does not lead to the generation of Aβ and does not contribute to the production of plaques. It is now thought that monomeric Aβ 1-42 is soluble. But the protein has a marked tendency to aggregate and easily forms insoluble aggregates called oligomers. One popular hypothesis is that these oligomers are the molecular species responsible for producing the pathological changes in the brain that are typical of AD.

As far as the tangles are concerned, they were found to be composed of the microtubule-associated protein tau, which is normally expressed in nerve axons but in AD becomes highly phosphorylated and aggregated into abnormal parahelical filaments (PHFs) in neuronal cell bodies. Over the years, there has been a lively debate as to whether Aβ or tau is responsible for the brain changes seen in AD. The group favoring Aβ became known as “Baptists” and the group favoring tau became known as “Tauists.” Although it is still not entirely clear which group is correct, most potential therapies aimed at treating AD have concentrated on the Aβ hypothesis which imagines that Aβ is the main culprit.

But if that is the case, what kind of therapy might be effective? The first idea to be floated was that drugs which blocked either the β- or γ-secretases that were involved in the release of Aβ from its precursor protein in the first place would do the job. A lot of time and effort was put into developing molecules that would perform this task but unfortunately, although they seemed to inhibit their target enzymes effectively and reduce the amount of Aβ in the brains of experimental mice or humans, clinical trials showed that they weren’t effective in treating the disease. Of course, it should be realized that clinical trials to test drugs for treating AD are themselves actually rather complicated. Do we expect a 90 year old with advanced dementia to actually get better? How about a younger person who is just starting to exhibit symptoms? What does “better” mean anyway? That the patient becomes normal again? Or perhaps that the rate of cognitive decline is slower? Exactly when to test a therapy for AD and what the expectations are for the drug involved is clearly an important consideration. If a potentially useful drug was tested on a group of patients where the cause of the disease had already produced irreversible damage, then no benefit would be observed whereas effects might have been seen if the drug had been tested earlier on in the course of the disease. Overall, considering the fact there are no therapies whatsoever for AD, most people think that a significant slowing of the rate of cognitive decline would be considered an important first step.

Advances in the science of human genetics have started to shed further light on the potential causes of AD and so suggest further potential routes for therapeutic intervention. After all, most patients who suffer from the disease don’t have the extremely aggressive early onset form of AD that is associated with “dominant” mutations in APP or presenilin that are inherited in a clearly Mendelian fashion. Rather, the major group of AD patients may have versions of many different genes that give them a greater “susceptibility” for getting the disease. In fact, for most people, whether they get AD or not ,is probably the result of a combination of these relatively modest genetic effects. Hence, knowing which genes produce these more subtle effects is clearly very important in the grand scheme of things. For example, quite some time ago it was shown that people who had a particular version of the apolipoprotein E gene were more likely to get AD and now there are a considerable number of such “risk” genes that have been identified. Each one might tell us something interesting about the natural history of the disease. Consider the gene that codes for the protein TREM2. TREM2 is usually expressed by cells called tissue macrophages that are central components of what is known as the innate immune response. Innate immunity is the body’s first response to anything that disturbs tissue homeostasis. This could be a toxin, an infectious agent, stress proteins expressed as warning signals by cells, or the detritus of dying cells. In the brain, tissue macrophages are called microglia. One thing that microglia can do is act as cellular garbage dumps that mop up pieces of dying cells or inappropriately aggregated proteins such as Aβ. It seems as though the protein product of the TREM2 gene has an important function in keeping microglia healthy so that they can go about their business of clearing up the brain. Mutations in TREM2 that are associated with AD risk seem to reduce the ability of TREM2 to do its job. Now, consider, if one of the things that microglia do is to remove aggregates of Aβ in the brain, then in people with TREM2 mutations, levels of Aβ would build up in the brain. In other words, accumulations of Aβ might be due to increased production of the protein through changes in the activity of the β- and γ-secretases, or to reduced ability to remove the protein as a result of something like a TREM2 mutation, or perhaps both things.

If accumulation of Aβ in the brain is an important factor in causing the symptoms of AD, then how exactly does this happen? Here again there are several ideas. One is that the formation of amyloid plaques is somehow toxic. After all, they are observed in flagrante delicto surrounded by the extensions (axons and dendrites) of dying nerve cells. On the other hand, it has also been argued that the plaques are really just garbage dumps that collect Aβ and that it is small aggregates of Aβ known as “oligomers” that actually produce the toxicity. At any rate, all of this suggests that rather than blocking the production of Aβ, if you could find a way of mopping it up and getting rid of it then this might also be a valuable therapeutic approach. How about using an antibody? Antibodies are usually used by the immune system to target problematic molecules associated with infectious agents or other foreign objects. They can do this with a great degree of specificity. An antibody that recognized Aβ might be able to remove it from the brain and get rid of it by a number of routes the body has at its disposal for destroying antibody/antigen complexes. This approach has been considered very seriously as a potential treatment for AD. If the antibody were given just as the disease was beginning to appear (known as the prodromal phase), it might prevent the entire cascade of resulting toxic events. We know from brain imaging studies that amyloid plaques begin to appear in the brain well before cognitive symptoms are seen in affected individuals. So, the theory is that intervening at this early stage might prevent the entire cascade of Aβ-related events from occurring—or, at least, intervening at an early stage of symptomatic disease might prevent its progression.

Here again there are a number of ways one could approach this problem. One type of immunization is known as “active” immunization: an appropriate antigen, a form of Aβ in this case, would be injected into a patient and over time the recipient’s immune system would generate antibodies against Aβ. This may take a while but might afford lifelong protection or at least very long-lasting immune protection against the effects of Aβ. Another kind of immunization is known as “passive” immunization. In this case, active antibodies are generated in a laboratory or other facility and then injected into the recipient. Such antibodies will begin working immediately but protection will wane as they are used up and then a further injection will be necessary. Many potent therapies these days rely on this method. For example, passive immunization against the cytokine TNF-α in preparations like Remicade are widely used for the treatment of inflammatory diseases. Overall, “biological” reagents like this have really revolutionized pharmacology in recent years.

Both active and passive techniques have been investigated in the treatment of AD. Generally speaking, the results have been disappointing. But one has to be careful here. Exactly which entity do you want your antibody to target? Given what we know about the natural history of plaque formation in AD, we would probably want to have an antibody that targeted aggregated forms of Aβ found in oligomers or plaques, rather than the soluble monomeric form of the protein. With this possibility in mind, a few years ago a company called Neuroimmune set out to find such an antibody by examining the white blood cells from older people that were not afflicted by AD. Maybe they already had such antibodies? The company, in collaboration with a second company called Biogen, obtained a positive result and prepared the antibody, which they named aducanumab, so that it could be used in clinical trials.

Biogen actually sponsored seven clinical trials investigating aducanumab in humans. The interim results from the first 165 patients participating in this trial were published in the high profile scientific journal Nature. All doses of aducanumab (given as monthly infusions into the bloodstream) were seen to significantly reduce amyloid plaques in the brain in a time- and dose-dependent manner compared with before treatment, whereas little to no change was seen in the placebo group after one year. The greatest reduction in plaques was seen at the higher doses. Aducanumab also appeared to slow the rate of cognitive decline. So overall, these Phase 1 trials were very promising and Biogen continued testing, continuing with Phase 2 and 3 trials—the ultimate test of a drug’s efficacy in the target human population. The phase 3 trials were aimed at assessing the efficacy of aducanumab, given once a month at low and high doses by infusion into the bloodstream, in treating the symptoms of Alzheimer’s disease. Based on the interim data, the hopes were high. However, an independent data-monitoring committee found that, based on the initial data coming out of the trial, the outcomes were unlikely to meet their primary objective, and so in March 2019 the trials with aducanumab were halted. That seemed to be the end of things for aducanumab. Or was it?

As it turned out, the decision to halt the trials hadn’t considered some of the data that were obtained later on in the trials. These data seemed to show that patients who had continued to take the drug at its highest dose did show a fairly impressive slowing in their rate of cognitive decline (23%). This was actually very promising and just a few weeks ago, the company made a rapid volte face declaring that they would, after all, be presenting their results to the Food and Drug Administration with a view toward bringing it to market. Although we don’t know if the FDA will approve the drug or how successful it will be, this is the cause of all the excitement as it would be the first example of a disease-modifying drug for the treatment of AD. It should be mentioned that patients who are treated with aducanumab can suffer from side effects including a drug-induced syndrome called ARIA (amyloid-related imaging abnormalities), headaches, urinary tract infections, and upper respiratory tract infections. However, if aducanumab works as advertised, it might be just the right option for somebody like Cassie Stuart’s Dad who is just starting to exhibit signs of what could be AD. In other words, there may be a lot of time during which an intervention like aducanumab could be used to significantly reduce the rate at which the disease takes hold.

Cats can help soothe patients with senile dementia

For more serious victims of AD, however, the picture is still bleak and may always be that way. Nevertheless, some things may help. If you can’t use aducanumab you can at least get a cat. It has been widely reported that companion animals have really significant calming effects on demented elderly patients. Furthermore, cats are much cheaper than a course of aducanumab treatment and are unlikely to give you ARIA or other side effects. Give me the cat!