Not since 2003 has a new medication been approved by the FDA for treatment of Alzheimer’s disease (AD). Fortunately, this long dry spell may be nearing an end. This article explores a variety of clinical trials that may one day provide new treatments and methods to more effectively manage Alzheimer’s disease.
The End of a Long Dry Spell
More than 400 clinical trials are currently looking at new treatments for Alzheimer’s disease (AD) and many of them are actively recruiting. Many of these studies are based on decreasing the harmful effects of a toxic protein called amyloid-beta in the brain, but others reflect a broadening range of possible treatment approaches based on other theories about AD.
Pharmaceuticals under study include both medications and dietary supplements. In addition to these, many studies are exploring non-pharmaceutical strategies. These include behavioral interventions, exercise, and physical treatments including acupuncture, electromagnetic devices, and even surgery. The representative trials discussed here are found in the registry of ongoing studies located at www.clinicaltrials.gov, which can be accessed for information about activity and enrollment.
The “amyloid hypothesis” is still regarded by many as a key explanation for AD’s development and progression. According to the amyloid hypothesis, the large amyloid precursor protein (APP) found on brain cell membranes undergoes an abnormal clipping by enzymes (called beta and gamma secretase), resulting in a toxic protein fragment called amyloid-beta.
Amyloid-beta, which circulates in blood and cerebrospinal fluid, can interfere with the part of the nerve cell, called the synapse, which is involved in transmitting electrical or chemical signals to other nerve cells. Furthermore, amyloid-beta sticks together and forms deposits in the brain, where in combination with an inflammatory reaction and brain cell death produce the amyloid plaques that are characteristic of AD.
Amyloid-beta is also thought by some researchers to induce the chemical change that eventually results in destruction of another important component of nerve cells’ internal structure. This results in neurofibrillary tangles, the other hallmark microscopic finding of AD.
The amyloid hypothesis has led to testing of medications which target the production, accumulation and persistence of amyloid-beta in the brain. Results, so far, have been mixed — but good enough to encourage further exploration.
Stopping the Production of Amyloid-Beta
The inhibition of enzymes that produce toxic amyloid, beta and gamma secretases, remains an active area of investigation. The first gamma secretase inhibitors proved too dangerous for use because of side effects. Selective beta secretase inhibitors have been better tolerated and are currently in testing. A partial list of these includes MK8931, JNJ54861911, and LY3314814.
Blocking the Accumulation of Amyloid-Beta
The accumulation of amyloid-beta into plaques has been targeted in various ways. One current trial, for example, is exploring a drug, called sargramostim, to reduce the accumulation of amyloid-beta.
Ramping Up the Immune System
Experimental medications have also been using the immune system to interfere with amyloid-beta accumulation, and to remove amyloid from the bloodstream, the cerebrospinal fluid, and even from brain plaques.
Nearly 20 years ago, amyloid was used in an “active vaccine” to stimulate the body’s natural development of disease-fighting antibodies. This effort failed for a couple of reasons. First, the production of the right kind of antibodies was unreliable due to the reduced responsiveness of the immune system in the older adults who received this treatment. In addition, vaccinated subjects who did react to the vaccine sometimes developed a life-threatening brain inflammation called aseptic meningitis.
A second generation of immunotherapy agents have relied upon “passive immunity,” which means that the patient receives an injection of pre-made antibodies that have a limited duration of action before they are eliminated or destroyed by the body.
Bapineuzumab, the first widely-tested passive immunotherapy, was withdrawn from development due to limited effectiveness and concern about adverse effects including tiny brain bleeds. Testing of solanezumab as a treatment for mild dementia was deemed unsuccessful. Newer agents, safer and possibly more effective, include aducanamab, crenezumab, gantenerumab, and others.
Though these injections are all passive immunotherapies, they vary significantly in their mechanism of attack on beta-amyloid. Variously, they attack amyloid-beta or plaques, in the peripheral circulation or in the brain.
A couple of immunotherapies are also being explored as preventive treatments in the normal elderly or those at significant genetic risk for AD (the DIAN study, for example).
The newest immunotherapy players represent a re-emergence of the active vaccine approach which, if successful, could be less costly and more lasting in its effectiveness. One experimental vaccine, called CAD106, induces immunity to amyloid-beta without exciting an autoimmune response. Another vaccine, called Lu AF20513, invigorates the aging immune system.
Some researchers working on AD have followed the dictum of famed bank robber Willy Sutton by “going where the money is,” or seems to be, by exploring therapies based on the amyloid hypothesis, while others have follow the well-known advice of 18th century moralist Samuel Palmer, who advised “Don’t venture all your eggs in one basket.” Competing theories about the development and progression of AD have opened up a wide range of therapeutic possibilities, many of which are currently being tested.
Aiming at Tau
One very strong school of researchers has insisted on the focusing on the protein called tau, which results in brain cell death through destruction of the neurons’ internal structure. TRx0237 is inhibits the accumulation of tau and is currently in testing. AADvac1 is a vaccine that targets abnormal tau protein.
Blood Sugar and the Brain
The brain’s damaged ability to use glucose (blood sugar) in AD is so important that some researchers call AD “Diabetes Type 3.” This observation has led to treatments aimed at repairing a metabolic defect by enhancing the effect of insulin. Intranasal insulin is in testing with promising early results. Improvement of blood sugar control is also the goal of trials using the drugs pioglitazone and exanatide.
The importance of inflammation in exacerbation of amyloid-beta’s neuron-destroying effects has led to trials of medications with anti-inflammatory properties. The combination treatment ALZT-OPT1 includes oral ibuprofen with use of the inhaled anti-inflammatory medication, cromolyn. Benfotiamine, the medication studied in another trial, is a derivative of thiamine with anti-inflammatory properties.
Improving Cognition with Serotonin
Serotonin neurotransmission failure is a demonstrated aspect of AD, and several experimental medications attempt to correct that problem. RVT-101 and LuAE58054 are two examples of medications that are in clinical trials. Altering the brain’s serotonin activity seems to help cognitive difficulties in schizophrenia, and may also prove helpful in cognitive difficulties associated with AD.
We all know that “We are what we eat,” and our brains can be helped or harmed by what we put in our mouths. Dietary supplements in current AD clinical trials include lithium water, omega-3 fatty acids with lipoic acid, the genistein, resveratrol, curcumin, and grape seed extract. Many of these attempt to reduce brain cell destruction through antioxidant and/or anti-inflammatory effects.
Another dietary trial includes the medical food, AC-1204, which contains long-chain triglyceride molecules that provide the insulin-resistant AD brain with an energy source alternative to glucose.
In light of the limited benefits seen with currently available medications, a range of behavioral interventions is also being tested in AD clinical trials. Preliminary results, being followed up in ongoing trials, support the value of yoga and physical activity. Hearing aids are being tested as a means of reducing sensory isolation experienced by AD patients with hearing problems. Behavioral management algorithms such as the DICE approach (Describe, Investigate, Create, Evaluate) are also being tested.
More invasive non-medication approaches in current testing include electroacupuncture, repetitive transcranial magnetic stimulation, direct cranial stimulation, and deep brain stimulation. Among the most invasive clinical trials, current research is also exploring the value of CERE-110 (adeno-associated virus-based delivery of nerve growth factor, delivered as an injection into the brain).
Treatments to Manage Agitation, Insomnia and Apathy
While efforts to prevent or treat the cognitive symptoms of AD remain a primary focus, researchers have also recognized that we need treatments for the non-cognitive behavioral symptoms of AD and other dementias. Preliminary results suggest that we may be on the verge of more effective approaches to managing these behavioral symptoms. In addition to the familiar medications being tested (memantine for agitation, aripiprazole for agitation, mirtazapine for sleep, methylphenidate for apathy), several new medications are also in clinical trials for AD behavioral symptoms.
Tetrahydrocannabinol (the active principle in marijuana) is being tested for agitation treatment. The dopamine blocking drug, brexiprazole, may have promise in treating agitation. Pimavanserin, reduces psychotic symptoms in Parkinson’s disease, is being tested for management of psychotic symptoms in a broader group of major neurocognitive disorders.
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With progress in these clinical trials, and others not included here, we will learn more about how to prevent, slow, and perhaps even someday reverse the devastating effects of Alzheimer’s disease. Participation in a clinical trial should be considered as a way of advancing knowledge and possibly benefiting from a treatment not yet widely available, but clinical trials are not without risk. In some cases, participation in a clinical trial delays treatment with a standard (if less effective) approach. Clinical trials, too, can expose a subject to unhelpful placebo treatment and/or toxic effects of an experimental medication, so participation should only be undertaken after a careful consideration of the risks and benefits as well as the other available treatment options.
For many people affected by AD, however, clinical trials offer both individual hope and an opportunity for altruism. One day, one or more of these new approaches may make a real difference in our ability to fight a disease that remains the most relentless of our major causes of death.
Information on Clinical Trials
- Learn more about clinical trials
- Understanding Alzheimer's Clinical Trials (Helpful Information and Interviews with Experts)
- Explore Alzheimer’s disease clinical trials:
- Alzheimer's Disease Clinical Trials Supported by BrightFocus
- Alzheimer’s Disease Toolkit (Helpful Information to Understand and Manage Alzheimer's Disease)
- Expert Information on Alzheimer's Disease (Articles)
- What's New in the Alzheimer's Treatment Pipeline (Article)
For More Detailed Information
- Learn more about The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU)
- Godyń J, Jończyk J, Panek D, Malawska B. Therapeutic strategies for Alzheimer's disease in clinical trials. Pharmacol Rep. 2016;68(1):127-38.
- Alzforum (http://www.alzforum.org) accessed 03/31/1
This content was last updated on: October 3, 2018
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