Since the year 2000, deaths from Alzheimer’s Disease (AD) have increased by 89% worldwide. With average life expectancy on the rise, the number of patients dealing with this condition – already around 47 million – is set to increase even further. With several major clinical trials for Alzheimer’s drugs targeting related pathways failing in rapid succession, drug companies are now branching out to research novel therapeutic avenues of treatment.
While the exact cause and order of pathological events in the development of AD is still uncertain, researchers have built their hypotheses upon certain pathological hallmarks of the disease, such as the accumulation of amyloid-beta plaques. Each has borne the scrutiny of whether it is truly causative, with the bulk of the field’s confidence resting upon the amyloid hypothesis. However, in recent years, this hypothesis has begun to fail, raising questions about amyloid’s role in AD.
Current treatment strategies offer mitigation of symptoms, but cannot prevent the progression of the disease; with several new strategies available, companies are placing their bets on which proposed mechanism of disease is most promising for therapeutic benefit.
Current treatments provide symptomatic, not curative, care
Current available treatments focus on simply treating symptoms of the disease, but do not alter disease course. There are four drugs on the market, three of which are acetylcholinesterase inhibitors.
Acetylcholinesterase works to break down the neurotransmitter acetylcholine, thus preventing this molecule’s signaling from reaching its downstream target. AD patients produce insufficient acetylcholine for healthy communication between neurons. Acetylcholinesterase inhibitors block the enzyme that breaks down acetylcholine, allowing more of this neurotransmitter to arrive at the receiving neuron. Three approved drugs, Pfizer’s Aricept, Shire Pharmaceutical’s Razadyne, and Novartis’s Exelon, slow the onset of symptoms, but only on the scale of months.
The fourth option available, often used in tandem with acetylcholinesterase inhibitors, is an NMDA antagonist. Glutamate, another neurotransmitter implicated in memory, stimulates the receiving cell via the NMDA channel. Glutamate serves as a key to unlock the excitatory NMDA channel into the receiving cell; when glutamate is plentiful, the channel remains open, causing the cell to become overstimulated and succumb to excitotoxicity and apoptosis.
Memantine (marketed as Ebixa by Lundbeck) regulates available glutamate by competitively binding to NMDA receptors, preventing excitotoxicity and preserving neurons. This treatment option also slows the onset of symptoms, though again only on the order of months.
Recently, companies have worked to develop treatments in these established pathways, such as Axovant’s intepirdine and Lundbeck’s idalopirdine; both are 5-HT6 antagonists which work to release acetylcholine, mimicking cholinesterase inhibitors. These compounds all failed to produce significant differences vs. a placebo for patients.
While acetylcholinesterase and NMDA inhibitors offer more hope to patients than a lack of therapies altogether, these options only work to prevent AD symptoms for a relatively short period of time. The FDA has approved no new drugs since 2003, however, underscoring the vast need for developing new disease-altering approaches.
Debunking the amyloid hypothesis
Within the brain, neurons are the cells that form connections and communicate information via synapses. The canonical explanation for Alzheimer’s disease is that neuronal communication is interrupted by the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles of the protein tau (NFT).
Amyloid plaques are formed from the cleavage of amyloid precursor protein (APP) into the smaller fragment amyloid beta, which aggregates into plaques in the extracellular space. These plaques are thought to be cytotoxic, inducing apoptosis via disruption of calcium ion transport. The prevailing hypothesis within the scientific community has historically been that amyloid-beta plaques are the causative factor for AD.
However, in recent years, billions of dollars have funded amyloid-hypothesis-based therapies that resulted in a number of high-profile clinical trial failures. In 2017 alone, several therapies were tested that targeted a variety of neurological pathways. Most of these therapies targeted the amyloid pathway, such as Merck’s verubecestat, an inhibitor of the APP cleavage enyzme BACE1.
Recently, Eli Lilly also conducted clinical trials for solanezumab, an antibody that binds to amyloid, resolubilizing it and facilitating its elimination. This unsuccessful attempt – along with Merck’s verubecestat – is the result of intense efforts chasing the amyloid hypothesis.
Mounting evidence suggests that amyloid may not actually play a driving force in the pathophysiology of AD. These failed clinical trials underscore the distinct possibility that amyloid may be a byproduct rather than a driver of disease.
It is interesting to note that various lines of mice, the model of choice for drug development pipelines, have been developed to mimic amyloid formation. At least four prominent strains (hAPP, PDAPP, PSEN1, and 3xTg, which develops both amyloid plaques and NFTs) all harbor genetic mutations in the amyloid pathway that are exceedingly rare in the general population and do not reflect the genetic milieu in the brains of over 99% of current AD patients. These mice develop plaques and cognitive deficits within six months; however, they may not adequately model the disease.
This contrasts starkly to the mice lines modeling other more common genetic risk factors for AD such as apoE4, a gene found in 60-80% of AD patients, which can take 12-16 months to develop cognitive deficits. With an open market and a rush for an effective treatment, the convenience of studying amyloid plaque formation makes a much more tractable hypothesis for researchers operating on a fixed budget and timeline.
Researchers have continuously “cured” AD in amyloid model mice, but these therapies have yet to translate to humans in clinical trials. In recent years, companies have begun to invest in more biologically relevant mouse lines, facilitating the development of non-amyloid therapies.
Tau: an alternative hypothesis
Both amyloid plaques and NFTs are seen in AD patients; however, it is not known whether these processes are driving forces or just the byproduct of this disease. Researchers are divided on whether treating the formation of plaques or NFTs would be most effective in combatting or curing Alzheimer’s.
NFTs are formed when the protein tau is post-translationally modified (PTM) into a toxic species (most often via acetylation or phosphorylation) and begins to aggregate in the cytoplasm. Typically engaged in cell signaling regulation, post-translationally-modified tau aggregates and interferes with neurotransmission.
Interestingly, it has been shown that a decrease in tau also renders amyloid plaques less toxic, as well as rescuing the deficits seen in apoE4 models. Researchers postulate that protein misfolding events are the causative agents for creating these NFTs, though there is as of yet no conclusive understanding of how tau PTMs could contribute to AD pathology.
Multiple companies are currently pursuing clinical trials for drugs targeting NFT formation as the cause of neurodegeneration, including Novartis’s repurposing of the tyrosine kinase inhibitor nilotinib. Nilotinib functions by clearing away cellular debris created by tau malfunctions and potentially by clearing away plaques as well.
Cortice Biosciences is also in the hunt for an effective NFT therapy; their candidate TPI-287 is a taxane derivative that stabilizes microtubules. There are other postulated methods for combatting AD via tau therapies, such as effecting an overall reduction in tau or inhibiting tau phosphorylation. However, these ideas have yet to yield viable drug candidates.
ApoE4: beyond the standard hypotheses
Recent findings in genetic risk factors associated with AD have pinpointed apolipoprotein E4 (apoE4) as the largest genetic risk factor, particularly relevant to late-onset AD (majority of cases). ApoE4 is one of three apolipoprotein isoforms present in humans, and has been implicated in the inhibition of neurite growth.
The apoE4 gene is present in about 25% of the population as compared to the other apolipoprotein isoforms. Individuals with two copies of apoE4 are more than five times as likely to develop late-onset AD than those without apoE4.
Smaller companies such as eScape Bio are investigating the potential of an apoE4-based therapeutic strategy. As recent findings have linked apoE4 to neuroinflammation and neurodegeneration, there is evidence to suggest that this route of research may prove fruitful.
Metabolic therapies: keeping the brain fed
Aside from those proffered by the tau, amyloid, and apoE hypotheses, there may be other underlying mechanisms of AD. The brain requires a consistent supply of glucose, metabolizing it into ATP to support its energy requirements. Lower levels of glucose are linked to a drop in cognition abilities, and diminished cerebral glucose metabolism (DCGM) is present in those diagnosed with AD.
Several metabolic therapies are currently in clinical trials, targeting the dysregulated pathways controlling glucose breakdown and lipid production/trafficking present in AD-afflicted cells. As metabolic therapies have been effective in treating diseases like cancer, a few companies are hopeful that already-approved drugs will offer treatment options that do not require the full length of clinical trials.
The FDA-approved ALS drug riluzole, currently in phase II trials, has been shown to upregulate the brain’s main glutamate transporter, EAAT2, which could prevent the cognition decline correlated with the decrease in EAAT2 expression. In addition, the thiamine derivative benfotiamine is undergoing clinical trials to investigate whether an increase thiamine prevents the development of DCGM.
Smaller companies such as M3 Bio are also investigating this treatment space. The relatively new startup has received $26 million in funding and has fast-tracked their first drug candidate, NDX-1017, into a clinical trial that began in October.
Inflammation and immunity: unleashing the body’s defense mechanisms
In addition to metabolic therapies, immunotherapies are a viable option for the treatment of AD – the body’s immune system offers an incredible defense mechanism against malfunctioning cellular machinery, and harnessing this to combat physiological problems could prove to be incredibly powerful.
For example, the FDA-approved Leukine® is a granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates white blood cell growth, eventually producing increased numbers of macrophages and dendritic cells. This therapy is currently in clinical trials for AD patients, and would present another fast-track drug opportunity if the study yields results.
Other therapies focus on the goal of reducing oxidative stress, such as VTV Therapeutics’ Receptor for Advanced Glycation Endproducts (RAGE) inhibitor (azeliragon) that also may inhibit amyloid plaque transport. Interaction of a ligand with RAGE results in continued inflammatory response, and RAGE itself has been implicated in AD pathogenicity in a variety of ways, from mediating amyloid-induced oxidative stress to tau hyperphosphorylation.
The path forward: without amyloid?
With effectively no trial data to lean on, the number of new non-amyloid therapies in the clinics shows that the community is beginning to believe that dedicating vast resources to the amyloid hypothesis may be wasteful and short-sighted. As the precise mechanism of AD is still yet to be elucidated, the best strategy for the market as a whole may be to diversify approaches via alternative theories.
A plethora of clinical trials are underway, most of which depart from the amyloid hypothesis. Results from these studies will hopefully provide telling evidence as to which, if any, of these alternative hypotheses are most accurate. Though elusive, a solution to Alzheimer’s Disease will be worth the investment.
Elizabeth Grossman is a science communication fellow at Biotech Connection – Bay Area and a graduate student at the University of California – Berkeley.
Have ideas for a BCBA article? Email email@example.com