The Tedious Efforts Towards an Alzheimer’s Therapy

This post is part 3 of a series. Parts 1 can be found here and part 2 can be found here.

We have medications for many chronic human diseases on hand. Basic and clinical research as well as efforts of the pharmaceutical industry were successful in providing measures against many health-threatening chronic conditions such as high cholesterol levels, diabetes, hypertension, and inflammations, just to name a few.

Frequently, defined chemical pathways are the targets of drug interventions, allowing the development, for instance, of enzyme inhibitors or replacement strategies. However, for a number of chronic age-related neurodegenerative diseases, the search for a therapy has been less successful so far. Dementia and Alzheimer’s Disease (AD), the most frequent cause of dementia, is a threat to all of us and a huge burden for our aging societies. Even after approximately 100 years of research, we are still not able to satisfactorily treat, stop, or cure this devastating brain disease. Admittedly, it is a very long journey from deciphering causes of a disease to having a drug against it on the pharmacy’s shelves. It is also a risky expedition—especially for the pharmaceutical industry—which usually takes many years and is very costly. Concerning AD, the development of drugs has never been and still is not driven by a full understanding of the disease but exemplarily by different disease hypotheses. Here, I summarize some of the key steps that led to the currently approved Alzheimer’s drugs (which I elaborated on in more detail in my book¹).

Six Alzheimer’s drugs have been approved; dozens are in the drug development pipeline

When we look at the present pipeline of compounds and the mechanisms that are being targeted at certain stages of drug development (clinical phases 1-3), the sheer number of target classes and compounds seems overwhelming. These drugs can be divided into groups and summarized as: (1) cognitive enhancers, (2) drugs targeting neuropsychiatric symptoms, (3) disease-modifying biologic agents, and (4) disease-modifying small molecules². Since the 1990s up until today, six Alzheimer’s drugs have been approved and are in use, four of which are considered as symptomatic therapy (targeting two key neurotransmitter systems), and two recently approved anti-amyloid antibodies are considered disease modifying therapy (DMT). Even though the anti-amyloid immunotherapy is currently the talk of the town, we should first look back and see where, how, and when Alzheimer’s therapy, in fact, started.

Alzheimer’s drugs targeting the cholinergic neurotransmission

In a short recap: AD was initially described as a deficiency of the neurotransmitter acetylcholine, which is known to mediate cognitive functions. In fact, a disturbance of cholinergic neurotransmission instantly affects cognitive processes in the human brain and is an early neurochemical change in AD. Historically, while in the late 1970s detailed neurochemical studies were rather rare, there was consensus that the measurable levels of the enzymes synthesizing and turning over the neurotransmitter acetylcholine (choline acetyltransferase and acetylcholine esterase) are decreased in Alzheimer’s pathology and that this decline is accompanied by a selective degeneration of cholinergic neurons. It all made sense: patients display a significant loss of cholinergic neurotransmission, which mediates cognitive function; therefore, AD must be a clear neurotransmitter deficiency disorder.

Parkinson’s Disease (PD) is yet another such neurotransmitter deficiency syndrome, in this case affecting the neurotransmitter dopamine and defining Parkinson’s as dopamine deficiency. Since PD was pharmacologically tackled with the replacement of dopamine neurotransmission (by applying L-dopa, the precursor molecule of dopamine), it appeared appropriate to walk that pharmacological path for Alzheimer’s therapy as well and to supplement with acetylcholine aiming to stabilize its levels. To achieve this and to ensure sustained cholinergic activity, researchers in the 1970s followed several competing strategies, including (1) administration of acetylcholine itself, (2) addition of the acetylcholine-producing key enzyme or a precursor molecule, and (3) reduction of acetylcholine breakdown through the inhibition of its degrading enzyme acetylcholine esterase in order to prolong its effects in the brain. We know today that the acetylcholine esterase inhibitors made the race.

Based on the conclusive and widely accepted cholinergic hypothesis of AD, application of acetylcholine esterase inhibitors was considered a first therapy. Consequently, the compound 1,2,3,4-tetrahydro-9-acridinamine, named tacrine, became the first FDA-approved drug for the treatment of AD in the U.S. in 1993 and a little later also in Europe. While tacrine was discontinued in the U.S. in 2013, the subsequently introduced acetylcholine esterase inhibitors donepezil (approved in 1996), rivastigmine (approved in 2000), and galantamine (approved 2001) are still in use.

However, after these drugs had been in clinical application for some time, the field largely agreed that they only had light to moderate symptomatic effects and acetylcholine esterase inhibitors were, in fact, not able to halt the disease. They also failed to prevent the progression (transition) of so-called mild cognitive impairment (MCI) to full-blown AD. In the search for further therapeutic avenues, the next pharmacological chapter was just around the corner. It began with targeting the glutamatergic neurotransmission system.

The glutamatergic hypothesis as a basis for an Alzheimer’s drug

Another neurotransmitter centrally involved in higher brain functions (learning and memory) is the amino acid glutamate (chemically L-glutamate), together with its receptors (especially the so-called N-methyl-D-aspartate-, NMDA‐receptor type). Glutamate is a building block of proteins but also the most abundant excitatory neurotransmitter in the vertebrate nervous system. More than 50 years ago, in addition to its excitatory receptor-mediated activities in the brain, possible neurotoxic functions of this neurotransmitter were uncovered. Unusual high concentrations of glutamate in the extracellular space can cause nerve cell death via an over‐activation of NMDA receptors. Glutamate’s neurotoxic activity is called excitotoxicity and was found to be associated with various neurological disorders, including acute (e.g., stroke) but also chronic neurodegeneration (e.g., AD).

Based on these discoveries, the glutamatergic-hypothesis of AD was formulated, and the NMDA-type glutamate receptor became a relevant pharmacological target from the 1990s on. In fact, glutamate and its NMDA receptor are pathophysiologically linked to a very wide range of neurological conditions. The drug memantine, a partial NMDA receptor blocker (‘antagonist’), initially developed for the treatment of stroke and other neurological diseases, was approved for the use as an Alzheimer’s therapy in the U.S. in 2003. While memantine’s mode of action was different than described for acetylcholine esterase inhibitors, it also turned out to have only limited clinical effects on some disease symptoms and only in a portion of treated individuals. Therefore, neither targeting the cholinergic nor the glutamatergic system were modifying the course of the disease; both displayed only symptomatic effects. It took another 18 years until the FDA approved the next generation of Alzheimer’s drugs in 2021.

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Anti-amyloid antibodies are considered a disease-modifying therapy

One can imagine the immense expectations and pressure on the Alzheimer’s research community, the research funding agencies as well as on the science politicians to come up with a convincing DMT approach while AD case numbers constantly increase. However, in order to develop DMTs for a disease, it is crucial to fully understand it. This is especially challenging when dealing with a disorder that starts early in life, unrecognized, and has to develop over decades until the first symptoms are tangible and detectable.

In the search for DMTs, big parts of the Alzheimer’s field focused on key pathological end stage hallmarks, such as extracellular amyloid beta peptide aggregates (plaques) and intracellular tau aggregates (tangles), thus defining Alzheimer’s as ‘plaques-and-tangles-disease’. The generation, aggregation, and deposition of amyloid beta was defined as the initial trigger acting upstream of tau pathobiology. The supposed sequence of pathological events, summarized in the ‘amyloid-cascade-hypothesis’ of 1992 and subsequent refinements, defined any measure to interrupt this sequence as a DMT. With assuming that amyloid is the culprit, it, of course, became the central target for pharmacological intervention and received utmost attention. Most approaches over the last 20-30 years when translated into the clinic, however, were disappointing. The inhibition of the enzymes that generate amyloid-beta was not successful. Tackling the amyloid beta aggregation process did not work. Removal of amyloid beta deposits by immunization with amyloid beta (active immunization approach) was not successful (or could not be further followed in humans due to severe side effects). Finally, also the injection of many different anti-amyloid antibodies targeting different biophysical forms of amyloid beta was clinically not successful in many cases.

However, more recently, for two of such monoclonal antibodies targeting amyloid beta (lecanemab and donanemab; passive immunization) moderate but significant clinical effects in delaying the cognitive decline were described for early onset AD. One part of the Alzheimer’s community welcomed these first positive clinical results with anti-amyloid antibodies—although being rather minor—and some may even interpret them as final proof of the amyloid-cascade-hypothesis. Other parts of the field remain highly skeptical considering the statistically calculated minimal effects as being clinically not relevant, in addition to the possible severe side effects, and the costs. The field is highly divided.

However, the fact is, lecanemab has already received its approval in 2023 and the approval of donanemab by the FDA is awaited soon. A predecessor anti-amyloid antibody called aducanumab received its highly controversial approval in the US already in 2021 but failed approval in Europe; as of 2022, it is still available but no longer seriously promoted by its manufacturer. In summary, today the pharmacy shelves in the U.S. presents a total of six Alzheimer’s drugs that are available, complemented by the combined use of acetylcholine esterase inhibitor (e.g. donepezil) and memantine. Whether the recently approved anti-amyloid antibodies will truly prove what many are hoping for, remains to be seen. In any case, we are still riding the bumpy road towards the development of an effective and convincing AD therapy, a road full of headwind and many surprises.