GOLD

Combination Therapy as a treatment for Alzheimer's Disease

I am researching the pathophysiology of Alzheimer's Disease as well as the efficacy of combination therapy for treatment of Alzheimer's. This includes a combination of approaches that target more than one cause of Alzheimer's.
Ziya Bhayani
Grade 8

Problem

Alzheimer’s disease is known to affect one in 10 people ages 65 and older. As per WHO, 50 million people aged 65 and older are living with Alzheimer’s or other pathologies involving dementia worldwide. This number is expected to double by 2030. These statistics are estimated to rapidly increase as the human lifespan increases. Currently it can be neither prevented nor reversed or treated. The problem is that there are no effective treatments for the disease. There are few FDA approved medications and drugs that treat the symptoms of Alzheimer's however there are no drugs that can reverse, prevent, or treat it. 

Upon studying the pathophysiology of this disease, I came to know that the formation of Amyloid-beta plaques that are caused by the cleavage of the Amyloid Precursor Protein (APP) by the beta-secretase is the root cause of the development and progression of Alzheimer's. None of the existing approved treatment options are targeting this cause. Clinical trials for BACE inhibitors have so far not yielded positive results that can allow their use for treatment on the general population. My project focuses on a different therapeutic approach that involves a combination of drugs that target more than one aspect of the disease such as neuro-inflammation, misfolded proteins, amyloid-beta plaques, and mitochondrial dysfunction for the treatment of Alzheimer’s Disease.

 


 

Method

1. Better understanding processes involved in the progression of AD like neuro-inflammation, misfolded proteins, amyloid-beta plaques, mitochondrial dysfunction, neurofibrillary tangles and other contributing elements of Alzheimer’s disease as well as the types, stages, and complications.

2.  Exploring inhibition of these processes from occurring at the onset.

3. Studying individual therapeutic approaches/drugs (monotherapy).

4. Studying clinical trials that are based on the concept of combination therapy involving two or more drugs that target two different causes/processes. 

5. Investigating the mechanism of the drugs that are currently being tested. 

6. Deriving conclusions from the literature reviews. Searching for additional supportive information e.g.:  facts/ diagnostics/ treatments using other strategies.

7. Proposing a possible combination of drugs that could be used and identifying possible areas that require further research.

 

 

Research

 

What is AD?

The brain relies on three key processes to survive. 

The first is communication. Your brain is sending signals to other neurons and receiving signals from others. This is done through chemical messengers in your brain called neurotransmitters. These signals contain instructions on what to do and is what tells the body to respond to stimuli. When a neuron receives signals from other neurons, it generates an electrical charge that travels down the length of its axon and releases neurotransmitter chemicals across a tiny gap, called a synapse. Neurotransmitters are chemical messengers that transmit a message from a nerve cell across the synapse to a target cell. The target can be another nerve cell, or a muscle cell, or a gland cell. They are chemicals made by the nerve cell specifically to transmit the message. Neurotransmitters are released from synaptic vesicles in synapses into the synaptic cleft, where they are received by neurotransmitter receptors on the target cell. Each neurotransmitter molecule then binds to specific receptor sites on a dendrite of a nearby neuron. This process triggers chemical or electrical signals that either stimulate or inhibit activity in the neuron receiving the signal. 

The second is Metabolism. It is the breaking down of chemicals and nutrients within a cell. To perform this function, cells require energy in the form of oxygen and glucose, which are supplied by blood circulating through the brain. The brain actually needs the most energy out of all other organs and the richest blood supply in the entire body because they need to send signals. The third key process is repair, remodel, and regenerate. Neurons live for 100 years in our brains so we need to constantly maintain and repair them. Neurons also continuously adjust, or “remodel,” their synaptic connections depending on how much stimulation they receive from other neurons. Remodeling of synaptic connections and neurogenesis are important for learning, memory, and possibly brain repair. 

A healthy brain shrinks in aging but doesn't lose neurons. In Alzheimer’s disease damage is widespread as many neurons stop functioning, lose connections with other neurons, and die. At first, Alzheimer’s disease typically destroys neurons and their connections in parts of the brain involved in memory, including the entorhinal cortex and hippocampus. Then affects areas in the cerebral cortex responsible for language, reasoning, and social behavior. Ultimately, the disease is fatal. 

Alzheimer’s disease is named after Dr. Alois Alzheimer who in 1906, noticed changes in the brain tissue of a woman who had died of an unusual mental illness. She had symptoms like memory loss, language problems, and unpredictable behavior. After she died, he examined her brain and found many clumps now referred to as amyloid-beta plaques which are insoluble proteins that accumulate because waste microglia cells and astrocytes cannot process and remove it. The second cause was tangles of fibers now called tau, or neurofibrillary tangles. These plaques build up between neurons, blocking pathways through which the communication happens. Without direction, neurons are helpless, they don’t receive energy, and they can’t repair themselves so they eventually die. Your brain loses connection with the rest of your body causing memory loss, speech impairment, and eventually the ability to be physically active. 

 

How are amyloid-beta plaques and neurofibrillary tangles created?

 

Amyloid-beta comes from this larger protein called Amyloid Precursor Protein (APP). APP plays roles both as an intact membrane protein and when broken into pieces. The intact protein is a receptor protein that sends signals through the G-protein system. APP also binds to many structural molecules outside cells, such as heparin and laminin, so it may play a role in cell adhesion. APP is also broken into several functional fragments by a set of dedicated proteases, termed secretases. A protease is an enzyme which breaks down proteins and peptides. Secretases are enzymes that "snip" pieces off a longer protein that is embedded in the cell membrane. Among other roles in the cell, secretases act on the Amyloid Precursor Protein (APP) to cleave the protein into three fragments.

The brain has APP which is cleaved by 3 secretases: alpha, beta, gamma. In a normal brain, the alpha secretase acts on APP and cleaves of sAPPa (secreted APP alpha). What is left is an 83 amino acid long membrane-bound C-terminal fragment called CTF83. In a brain with Alzheimers’s, an enzyme called beta-secretase acts on APP and cleaves it into sAPPb (secreted APP beta). What is left is a 99 amino acid long membrane-bound c-terminal fragment called CTF99. In normal signaling, CTF83 is further cleaved by the gamma-secretase complex made up of PSEN1, Pen-2, APH-1, GSAP, and NCT. Cleavage of CTF83 leads to the generation of APP intracellular domain (AICD fragment). AICD fragment translocates to the nucleus where it affects the transcriptional regulation of several proteins, and drives neuroprotective pathways. It is also important to know that sAPP alpha gets secreted from the neurons and drives normal synaptic signaling leading to synaptic plasticity, learning and memory, neuronal survival, and emotional behaviours. In AD, gamma-secretase complex is also assembled but cleaves CTF99 fragment into an AICD fragment and an abeta 40/42 peptide. AICD is again translocated to the nucleus where it affects transcriptional regulation of several proteins and drives neuroprotective pathways. The Abeta 40/42 peptide however is involved in downstream pathways related to AD. This peptide misfolds resulting in a sticky exterior that attaches to other proteins as well as other abeta peptides forming amyloid-beta plaques. 

Tau is a protein that helps stabilize the internal skeleton of nerve cells (neurons) in the brain. This internal skeleton has a tube-like shape through which nutrients and other essential substances travel to reach different parts of the neuron. In Alzheimer’s disease, an abnormal form of tau builds up and causes the internal skeleton to fall apart. 

Tau accumulation has been shown to promote brain cell damage and death in Alzheimer’s and other dementias, but the exact processes that lead to this toxicity are unclear. Some studies suggest stress in the brain cell's endoplasmic reticulum (ER), the part of the cell where proteins are produced, may play a role in the toxic effect of tau tangles and abnormal tau. Results of these studies may clarify how tau toxicity develops in the brain and promotes brain cell damage in Alzheimer's. The results may also suggest new avenues to investigate for therapies that may prevent or slow the brain changes of Alzheimer's and other dementias.

What treatment strategies are being implemented? 

Treating dementia has become a major challenge in clinical practice. Presently, acetylcholinesterase inhibitors are the first-line drugs in the treatment of Alzheimer’s disease (AD). These options are now complemented by memantine, which is approved for the treatment of moderate-to-severe AD. Cholinesterase inhibitors aim to increase communication between the nerve cells to try to improve the symptoms of Alzheimer’s. Cholinesterase inhibitors work by increasing levels of acetylcholine, a chemical messenger involved in memory, judgment and other thought processes. Certain brain cells release acetylcholine, which helps deliver messages to other cells. After a message reaches the receiving cell, various other chemicals, including an enzyme called acetylcholinesterase, break acetylcholine down so it can be recycled. Alzheimer’s disease damages or destroys cells that produce and use acetylcholine, thereby reducing the amount available to carry messages. A cholinesterase inhibitor slows the breakdown of acetylcholine by blocking the activity of acetylcholinesterase. By maintaining acetylcholine levels, the drug may help compensate for the loss of functioning brain cells. Compared with placebo, positive effects of AChE inhibitors are shown with regard to cognition and global impression of the physician. 

These drugs have been approved for use in mild to moderate Alzheimer’s disease. In Germany, three different cholinesterase inhibitors are currently available: donepezil, galantamine and rivastigmine. They are taken in the form of tablets. Rivastigmine is also available in a patch. Here the drug is absorbed into the body through the skin. The studies show that the cholinesterase inhibitors donepezil, galantamine and rivastigmine can slightly delay the loss of mental abilities in people who have mild to moderate Alzheimer’s disease. For instance, some of the people with Alzheimer’s who regularly took one of these medications were able to remember things more easily. In clinical trials of all three cholinesterase inhibitors, people taking the medications performed better on memory and thinking tests than those taking a placebo, or inactive substance. 

The other FDA approved drugs are Memantine.  Memantine (Namenda® ) is prescribed to improve memory, attention, reason, language and the ability to perform simple tasks. It was the first Alzheimer’s drug of the NMDA receptor antagonist type approved in the United States. It is used to treat moderate-to-severe Alzheimer’s. Memantine appears to work by regulating the activity of glutamate, a chemical involved in information processing, storage and retrieval. Glutamate plays an essential role in learning and memory by triggering NMDA receptors to let a controlled amount of calcium into a nerve cell. The calcium helps create the chemical environment required for information storage. Excess glutamate, on the other hand, overstimulates NMDA receptors so that they allow too much calcium into the nerve cells. That leads to disruption and death of cells. Memantine may protect cells against excess glutamate by partially blocking NMDA receptors. 

One clinical study showed that people taking memantine showed a small but statistically significant improvement in their mental function and ability to perform daily activities. Another study randomly assigned participants to receive either 10 mg of memantine twice a day or a placebo in addition to donepezil (Aricept), a cholinesterase inhibitor. Those receiving memantine showed a statistically significant benefit in mental functioning and performing daily activities, while participants taking donepezil plus placebo continued to decline. 

The last FDA approved drug option for Alzheimer’s treatment is Namzaric® , a combination of donepezil and memantine, for the treatment of moderate-to-severe Alzheimer’s in people who are taking donepezil hydrochloride 10 mg. Individuals taking Namzaric may see an improvement in cognition and overall mental function, and a temporary slowdown in the worsening of symptoms. However, there is no evidence that Namzaric prevents or slows the underlying disease process in patients with Alzheimer's disease.

These drugs can only treat the cognitive symptoms of Alzheimer’s. They are unable to prevent, reverse, or treat the disease itself. In order to treat Alzheimer’s, the drug needs to target one of the causes of this disease. There are many monotherapeutic approaches that individually target the causes of AD. 

Inflammatory processes involving cytokines and Glia cells play an important and complex role in the pathogenesis of Alzheimer's. Chronic inflammation is referred to as slow, long-term inflammation lasting for prolonged periods of several months to years. Generally, the extent and effects of chronic inflammation vary with the cause of the injury and the ability of the body to repair and overcome the damage. Neuroinflammation control with varying combinations of low-dose corticosteroids, anti-inflammatories, microglial suppressors, and nutritional supplements. Spinal fluid flow exercises including walking arm swings, upper body gyration, and deep breathing.  In the Border zone of early diffuse plaques astrocytes can be found functioning as antigen-presenting cells under specific conditions. In the stage no signs of neurodegeneration are parent but primary synaptic changes are perceptible. As a result the membrane attack complex is activated damaging the Integrity of the cell membrane. In addition to the anti-inflammatory effect NSAIDs direct effect on amyloid formation could be relevant for selecting them as potential treatment in AD. The recognition that NSAIDs can bind to and activate the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-y Has offered an additional explanation for the action of these drugs in Alzheimer's. Ppar-y agonists were shown to play a critical role in regulating the inflammatory responses of microglia and monocytes to AB.

Another monotherapeutic approach targets Cholesterol lowering therapy. The production amyloid-beta depends on the availability of cholesterol in the nerve cells. Balance of the alpha and beta secretase activity is linked with cellular lipid composition. High cellular cholesterol levels increase amyloidogenic processing of amyloid precursor protein by beta-secretase whereas low levels of cholesterol levels increase the physiological metabolism of APP by a-secretase. By this mechanism, a depletion of cholesterol from neuronal membranes could be a therapeutic approach for the treatment of AD.

Researchers are investigating ways to prevent tau protein from forming into tangles, which ultimately destroys the neuron. One potential therapy in clinical trials that targets tau protein is AADvac1. AADvac1 is a vaccine that stimulates the body’s immune system to attack the abnormal form of tau protein that causes the internal skeleton of neurons to fall apart. If successful, it has the potential to help stop the progression of Alzheimer’s disease. 

The next monotherapeutic approach targets the amyloid cascade, BACE inhibitors. BACE inhibitors are drugs to block the beta-secretase enzyme from cleaving the Amyloid-Precursor Protein. It has been shown that deletion of BACE-1 (beta-site amyloid precursor protein cleaving enzyme 1) abrogates AB production and betters cognitive/behavioral deficiencies, as observed in transgenic mice overexpressing human APP with familial AD mutations, indicating that inhibition of BACE1 has a direct effect. A rare human mutation at the BACE1 cleavage site of APP results in a 40% decrease in Aβ production in vitro, a significantly reduced propensity for Aβ to aggregate, a five- to seven-fold reduced risk of developing AD, and greater resilience to cognitive dysfunction in elderly individuals, implying that BACE1 cleavage alone appears to be beneficial in the human brain. 

Inhibition of BACE1 directly reduces Aβ-mediated impairments in synaptic transmission. Deletion of BACE1 in mice appears to have a minor impact on mouse growth or overall functions, perhaps related to the fact that most BACE1 substrates are also shed by α-secretase. Direct inhibition of γ-secretase, another strategy to reduce Aβ generation, is now recognized to be more challenging due to the indispensable physiological roles of γ-secretase, leading investigators and many companies to focus on BACE1 inhibitors, which act upstream of γ-secretase in Aβ generation. Thus, BACE1 is recognized as a better-positioned target for treating AD patients. 

Upon studying the clinical trials from BACE inhibitors, my observation was that most BACE 1 drugs are safe in terms of Phase 1 trials. Most BACE inhibitor drugs have improved AB 40/42 levels in CSF, and plasma. They were also effective in mice/ animal brains. Most drugs were discontinued in phase 2 or 3. Even the slightest level of cognitive symptoms of AD might be too late for BACE inhibitors to work, looking at how most of the trials were discontinued due to inefficiency of drugs. BACE inhibitors need to be administered long before mild symptoms of AD are observed. They need to be given several years before onset symptoms occur. BACE inhibitors may not be the most effective way of treatment if they alone are unable to reverse/ treat the cognitive symptoms as well as other deficits in the brain. 

A combination of drugs including cholinesterase inhibitors/ Memantine as well as other drugs might be a better/ more effective combination provided these drugs are compatible with one another and are administered slowly. The combination of drugs is targeting the decline of cognitive symptoms.

Combination therapy for Alzheimer’s. 

There are two disease modifying therapies (DMTs) currently in phase III trials that address two targets and represent valid combination therapies: ALZT-OPT1 and Gamunex (immune globulin intravenous (human), 10%; Grifols Therapeutics, Clayton, NC, USA). The ALZT-OPT1 trial, a combination regimen with cromolyn (anti-amyloid agent) and ibuprofen (anti-inflammatory agent), is enrolling patients with early AD who are either receiving or not receiving standard-of-care agents. Cromolyn is a treatment for asthma approved by the US Food and Drug Administration (FDA) that bears structural similarity to other anti-amyloid agents and is likely to cross the blood-brain barrier. Cromolyn reduced Aβ fibrilization and oligomerization in vitro and reduced Aβ40 and Aβ42 monomer concentrations in the mouse brain; oligomerization and fibrillation were unchanged in vivo. ALZT-OPT1 is a true combination trial in that the combination targets multiple disease pathways (amyloid and inflammation) and includes multiple methods of administration (intranasal inhaler for cromolyn and oral tablet for ibuprofen). ALZT-OPT1 is also an add-on study because it allows patients to continue standard-of-care treatments on stable doses.”

Although single agent therapy has the advantage of simplicity, fostering patient compliance and allowing straightforward identification of the source of adverse effect, monotherapy also has substantial limitations. Many diseases are a product of multiple pathophysiological pathways. One drug blocking a single step in a complex pathogenic network often cannot block all crucial disease-propagating mechanisms. 

Combining therapeutic agents may allow for lower doses of the individual agents, reducing costs and side effects. Innovative and adaptive clinical trial designs may also capture the potential evolution of therapeutic combinations over the long and complex course of disease progression, with one set of agents appropriate for preclinical AD, another for early-stage AD, and yet another for AD dementia.

 

Data

https://www.alzforum.org/therapeutics/verubecestat Verubecestat:

  •  Phase 1 trials tested single doses up to 450 mg and multiple doses from 12 to 150 mg/day. 
  • Two Phase 1/2 dose-ranging trials further evaluated the tolerability and pharmacology of single and multiple doses, respectively, in 88 healthy adults. 
  • At the 2012 AAIC conference in Vancouver, Canada, MK-8931 was reported to have been generally safe, without discontinuations due to side effects, and to have reduced CSF Aβ concentration in AD patients.
  • These studies used repeated CSF sampling, which found that CSF Aβ was reduced by up to 90 percent (see Jul 2012 conference news)
  • In November 2012, Merck started EPOCH, an 18-month Phase 2/3 trial comparing 12, 40, or 60 mg/day of MK-8931 given as once-daily tablets to placebo in people with mild to moderate AD
  • EPOCH started out treating 200 people in Phase 2 and, after an interim safety analysis, expanded to Phase 3 with a total of 2,221 participants. This trial included conventional cognitive and functional primary outcomes, as well as substudies for biomarker outcomes indicating changes in brain amyloid, CSF tau levels, and brain volume.
  • On 14 February 2017, Merck announced a premature end to this trial following an interim analysis . A subsequent paper further detailed the safety data, noting particularly that while psychiatric side effects did not get worse over time, falls and injuries did
  • Although a dramatic reduction of Aβ40, Aβ42, and sAPPβ in CSF of up to 80% was detected and a small reduction in plaque load was confirmed by amyloid PET in participants taking the drug, the clinical trial was terminated in February 2018, with verubecestat exhibiting no improvement in cognitive function in AD patients cited as the reason.

The results of this drug trial suggest that BACE1 inhibitors need to be given several years before the onset of AD symptoms.

 

Lanabecestat: https://www.alzforum.org/therapeutics/azd3293

  • Lanabecestat, a small-molecule, orally administered BACE1 inhibitor developed by AstraZeneca
  • The drug has a slow off-rate (estimated half-life of 9 h for BACE1) , which may result in a prolonged reduction of Aβ.
  • The phase I study, begun in 2014 and trial results demonstrated excellent safety, tolerability, and metabolic profiles in elderly healthy volunteers and in AD patients with mild cognitive impairment
  • Like Merck’s verubecestat, lanabecestat also strongly decreased the CSF Aβ level in the treated group.
  • Phase II/III clinical trials recruited over 1400 participants and were planned to last up to 54 months with variable doses; they attempted to measure efficacy and safety in humans by analyzing results such as amyloid PET scans, CSF Aβ levels, and CSF amyloid inclusion.
  • The clinical development program of this compound largely skipped Phase 2. Instead of running a medium-size Phase 2 followed by separate, larger confirmatory Phase 3 trials, the sponsors opted for a large, pivotal Phase 2/3 trial called AMARANTH.
  • This trial compared AZD3293 to placebo given for two years in 2,202 patients who met NIA-AA criteria for MCI due to AD or mild AD.
  • Each participant or his or her partner was required to report worsening in the past six months, and the participant's MMSE had to be above 21 at screening. 
  • In July 2016, a second Phase 3 trial started up. Called DAYBREAK-ALZ and conducted at 251 locations worldwide, it enrolled 1,899 patients with mild AD dementia as defined by an NIA-AA diagnosis of probable AD with a biomarker evidence of brain amyloid and an MMSE of 10 to 26.
  • This four-arm trial compared two once-daily doses given for three years to two groups who start out on placebo for 18 months and then switch to either the low or high dose for the second half of the trial. 
  • On June 12, 2018, AMARANTH and DAYBREAK-ALZ were discontinued due to lack of efficacy determined at an interim futility analysis
  • Lanabecestat reduced blood Aβ40 and Aβ42 levels by 70 to 80 percent in both trials. 

Similar to that of verubecestat, the lesson learnt from this announcement is that the appearance of even mild symptoms may be too late in the disease continuum for a BACE1 inhibitor to be efficacious.

 

Atabecestat https://www.alzforum.org/therapeutics/atabecestat

  • Daily administration of atabecestat 5–150 mg in healthy elderly and young participants for up to 14 days showed significant and consistent reduction of Aβ (up to 90% in the 90 mg cohort) in both plasma and CSF
  • Although minor adverse effects such as headache and back pain were noted in the phase I trial, it was deemed safe enough to advance to phase II trials.
  • a multicenter phase II trial, recruited 114 pre-dementia individuals to determine the tolerability and long-term safety of atabecestat, including double-blind treatment for 6 months.
  •  Atabecestat was found to successfully reduce both plasma and CSF levels of Aβ1-37, Aβ1-38, Aβ1-40, and Aβ1-42 in a dose-dependent fashion, while levels of sAPPα were conversely increased. 
  • In a separate trial called EARLY that was launched in 2015, participants are asymptomatic but at risk of developing Alzheimer’s dementia and were intended to receive drug or placebo once daily for up to 4.5 years with continuous monitoring of cognitive scales. 
  • Unfortunately, observation of elevated liver enzymes in two patients led Janssen to announce the discontinuation of this trial on 17 May 2018. 

 

Elenbecestat (E2609) https://www.alzforum.org/therapeutics/elenbecestat:

  • Elenbecestat (E2609), originally developed by Eisai as a small-molecule inhibitor of BACE1, is currently in clinical trials co-developed with Biogen.
  • A phase I trial reported that a single dose of 50 mg in 73 healthy participants (either gender, from age 30 to 85 years in six separate cohorts) was well-tolerated and safe.
  • “A single oral ascending-dose study of 5–800 mg and a 14-day multiple oral ascending-dose study of 25–400 mg showed that elenbecestat could significantly reduce plasma or CSF Aβ levels by as much as 92%: plasma Aβ relative to baseline was 52% at 5 mg and 92% at 800 mg”
  • In addition, by comparing different doses to placebo in mild cognitive impairment/prodromal patients or two doses in subjects with mild AD dementia, elenbecestat was found to delay clinical symptoms at the endpoint of the trial
  • A phase IIa trial concluded that of elenbecestat 50 mg/day was safe and consistently reduced CSF Aβ by about 70%.
  • Thus, a standard phase III trial called MISSION AD was initiated in November 2016 and MISSION AD2 was initiated in January 2017, enrolling a total of 1330 early AD subjects. 
  • Encouragingly, and unlike earlier mentioned discontinued trials, Biogen announced in June 2018 that the 18-month-long phase II study had revealed less decline in functional cognition in addition to a significant reduction in Aβ levels, quantified by amyloid PET imaging, in patients with mild to moderate form of AD.                    
    • Another method for targeting the amyloid cascade is the use of humanized or fully human monoclonal antibodies (mAbs) that bind and mount an immunologic response against the Aβ peptide, leading to increased amyloid clearance. Based on promising results in phase I/II trials, three Aβ mAbs (aducanumab, gantenerumab, and crenezumab) are being investigated in placebo-controlled phase III trials as add-on therapy in patients with early (i.e., prodromal) or mild AD. These trials are estimated to be completed between 2019 and 2022.

Data of Individual anti-inflammatory

  • According to the neuroinflammation hypothesis underlying AD, there is a lower incidence of AD among users of chronic non-steroidal anti-inflammatory molecules (NSAIDs) 
  • Anti-inflammatory compounds, inhibiting COX activity, Naproxen and Celecoxib have been tested in clinical trials against AD.
  • Naproxen, a non-selective COX inhibitor was administered (220 mg/twice day for two years) to 195 pre-symptomatic AD subjects (aged 55+) with a familial history of AD. The progression of the disease was evaluated with the Alzheimer’s Progression Score (APS). Naproxen reduced the rate of the APS, though not significantly
  • Celecoxib, a selective COX-2 inhibitor, was administered (200 mg/twice day for 2 years) in 677 pre-symptomatic subjects (70+) with at least one first-degree relative with AD. No improvement in the cognitive symptoms in the Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT) in the AD patients compared to the placebo group was found. 
  • Furthermore, the specific TNF-α inhibitor, Etanercept, was evaluated in a small group of 41 AD patients (55+) with mild to severe AD (SMMSE score between 10 and 27), to test its anti-inflammatory effect and subsequent improvement of cognitive function. 
    • The weekly 50 mg subcutaneous administration was well tolerated; however, after 24 weeks of treatment, Etanercept did not show significant beneficial effects in cognition, behavior, systemic cytokine levels or global function compared to the placebo-treated group
  • The failure of this clinical trial involves many factors, including insulin resistance  thus inhibiting specifically the TNF-α action may not be sufficient to counteract the inflammasome activity, and hence, to effectively prevent disease, perhaps due to the short period of time of assays.

Data of cholinesterase inhibitor

  •  These drugs have been approved for use in mild to moderate Alzheimer’s disease. In Germany, three different cholinesterase inhibitors are currently available: donepezil, galantamine and rivastigmine. They are taken in the form of tablets. Rivastigmine is also available in a patch. Here the drug is absorbed into the body through the skin.
  • Galantamine appears to stimulate the release of acetylcholine and strengthen the way certain message-receiving nerve cells respond to it. Rivastigmine may block the activity of another enzyme involved in breaking down acetylcholine.
  • In clinical trials of all three cholinesterase inhibitors, people taking the medications performed better on memory and thinking tests than those taking a placebo, or inactive substance
  • Some of the people with Alzheimer’s who regularly took one of these medications were able to remember things more easily.

Data of Memantine

  • One clinical study showed that people taking memantine showed a small but statistically significant improvement in their mental function and ability to perform daily activities.
  • But study participants with the lowest cognitive functioning showed no improvement on either daily activities or overall function.
  •  Another study randomly assigned participants to receive either 10 mg of memantine twice a day or a placebo in addition to donepezil (Aricept), a cholinesterase inhibitor.
  • Those receiving memantine showed a statistically significant benefit in mental functioning and performing daily activities, while participants taking donepezil plus placebo continued to decline.

Data of Combination of memantine and donepezil:

  •  Namzaric® , a combination of donepezil and memantine, was approved by the FDA for the treatment of moderate-to-severe Alzheimer’s in people who are taking donepezil hydrochloride 10 mg.
  • Individuals taking Namzaric may see an improvement in cognition and overall mental function, and a temporary slowdown in the worsening of symptoms. However, there is no evidence that Namzaric prevents or slows the underlying disease process in patients with Alzheimer's disease.

Data of Combination therapies:

There are two DMTs currently in phase III trials that address two targets and represent valid combination therapies: ALZT-OPT1 and Gamunex (immune globulin intravenous (human), 10%; Grifols Therapeutics, Clayton, NC, USA).

  • The ALZT-OPT1 trial, a combination regimen with cromolyn (anti-amyloid agent) and ibuprofen (anti-inflammatory agent), is enrolling patients with early AD who are either receiving or not receiving standard-of-care agents
  • Cromolyn is a treatment for asthma approved by the US Food and Drug Administration (FDA) that bears structural similarity to other anti-amyloid agents and is likely to cross the blood-brain barrier
  •  Cromolyn reduced Aβ fibrilization and oligomerization in vitro and reduced Aβ40 and Aβ42 monomer concentrations in the mouse brain; oligomerization and fibrillation were unchanged in vivo. ALZT-OPT1 is a true combination trial in that the combination targets multiple disease pathways (amyloid and inflammation) and includes multiple methods of administration (intranasal inhaler for cromolyn and oral tablet for ibuprofen). ALZT-OPT1 is also an add-on study because it allows patients to continue standard-of-care treatments on stable doses.”
  • Combination therapy approaches

 

 

 

 

 

 

 

 



 

Conclusion

Given the complexity of AD, treatment of patients remains challenging. The currently approved treatments for AD are limited to cholinesterase inhibitors and memantine or the combination of these agents.

 The high failure rate of the therapies in development for AD in large part comes from the complex pathologic causes of the disease, as well as our incomplete understanding of the relationships among the numerous pathways involved in development of AD and subsequent neurodegeneration, and the ineffectiveness of available agents.

Although single agent therapy has the advantage of simplicity, ensuring patient compliance and allowing straightforward identification of the source of adverse effect, monotherapy also has many limitations. AD is a product of multiple pathophysiological pathways. One drug blocking a single step in a complex pathogenic network often cannot block all crucial disease-propagating mechanisms. 

Combining therapeutic agents may allow for lower doses of the individual agents, reducing costs and side effects. Innovative and adaptive clinical trial designs may also capture the potential evolution of therapeutic combinations over the long and complex course of disease progression, with one set of agents appropriate for preclinical AD, another for early-stage AD, and yet another for AD dementia.

Other non-therapeutic factors such as genetics, diet, lifestyle, health parameters like obesity, diabetes, high cholesterol, sleep patterns, etc, need to be studied in order to   determine impact on the cause and progression of this disease. A few studies conducted in this area have shown the importance of maintaining proper health ie. normal cholesterol levels, average weight, blood glucose, adequate sleep, and daily exercise. Another area of importance is keeping your brain active. The experience of Alzheimer’s is ultimately a result of losing synapses. Engaging in mentally stimulating activities increases your cognitive reserve because this creates an abundance of synaptic connections. 

BACE inhibitors have been unsuccessful so far and one of the reasons why is because the appearance of even mild symptoms may be too late in the disease continuum for a BACE1 inhibitor to be efficacious. Hence, another step would be to identify individuals that are at risk of developing Alzheimer’s. These would be people with a family history of Alzheimer’s, those carrying the APOE4 gene, people with Cardiovascular diseases, high cholesterol, and diabetes. Having one or more of these risk factors increases the probability of one’s development of Alzheimer’s. Identifying individuals at risk can then allow for preventative measures to be taken and the administering of preventative agents such as BACE inhibitors. 

After completing my research, I have come to the conclusion that having clinical trials for treatments on high risk individuals started early, with a combination of agents like BACE inhibitors and amyloid antibodies, as well as cholinesterase inhibitors and memantine along with other combination drugs could identify a new therapeutic approach. The data gathered from my research proves that a combination of approaches that target more than one cause of AD such as neuro-inflammation, misfolded proteins, amyloid-beta plaques, and mitochondrial dysfunction will be most effective in the treatment of Alzheimer’s Disease, thus proving my hypothesis correct.

 

Citations

Schmitt B, Bernhardt T, Moeller HJ, Heuser I, Frölich L. Combination therapy in Alzheimer's disease: a review of current evidence. CNS Drugs. 2004;18(13):827-44. doi: 10.2165/00023210-200418130-00001. PMID: 15521788.

Das B, Yan R. A Close Look at BACE1 Inhibitors for Alzheimer's Disease Treatment. CNS Drugs. 2019;33(3):251-263. doi:10.1007/s40263-019-00613-7

https://www.alz.org/alzheimers-dementia/what-is-alzheimers

https://www.alz.org/media/Documents/fda-approved-treatments-alzheimers-ts.pdf

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Acknowledgement

I would acknowledge the following people:

Sudha Tallavajhula, MD: Neurologist, Associate Professor, Department of Neurology, McGovern Medical School, UTHealth

Sapna Padania: Research Scientist II at InMed Pharmaceuticals

Asif Jafferani:Honorary Assoc/Fellow, Cardiovascular Medicine Staff