Swank Center for Memory Care and Geriatric Consultation, ChristianaCare
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.
More than 600 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.
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 but so far none has proven efficacious.
The accumulation of amyloid-beta into plaques has been targeted in various ways.
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 although it is still being tested as a preventive agent in high-risk individuals. Several more recent monoclonal antibodies have failed in their clinical trials, but hope was recently revived for the success of one of them. Aducanumab’s data failed a “futility analysis” in March of 2019 but subsequent data analysis including additional data was encouraging enough to support an FDA application for treatment of Alzheimer’s disease. The FDA’s decision is anticipated late in 2020. If aducanumab is approved, additional immunotherapeutic agents are all the more likely to be submitted.
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.
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.
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.
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 or methylene blue, was tested on the basis of its ability to inhibit the accumulation of tau but early enthusiasm was not supported by trial results. AADvac1 is a vaccine that targets abnormal tau protein. Several trials have been completed but results not yet available.
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 continues in testing with some promising early results.
The importance of inflammation in exacerbation of amyloid-beta’s neuron-destroying effects has led to trials of medications with anti-inflammatory properties. A trial has been completed, but results not yet reported, for combination treatment with oral ibuprofen and an inhaled anti-inflammatory medication, cromolyn. Results are also anticipated from a completed trial of benfotiamine, a derivative of thiamine with anti-inflammatory properties.
Serotonin neurotransmission failure is a demonstrated aspect of AD, and several experimental medications attempt to correct that problem. 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, resveratrol, curcumin, and grape seed extract. Many of these agents attempt to reduce brain cell destruction through antioxidant and/or anti-inflammatory effects.
A trial of 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, failed in 2017.
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.
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, brexpiprazole, may have promise in treating agitation. Pimavanserin, which 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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James Ellison, MD received his medical degree from UCSF in 1978 and trained in psychiatry at the Massachusetts General Hospital (1979-1982).
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