Experimental Treatments for Alzheimer's Disease
Approved therapies for Alzheimer’s disease do not address the underlying cause of the disease, but instead treat only the symptoms. However, there is a vast array of experimental treatments that are being investigated in the quest to find a cure for the disease. Many of these treatments aim to modify the disease process itself. Some of the potential treatments currently in the pipeline are summarized below.
Although memory loss and cognitive function decline are well-known symptoms of Alzheimer’s disease, patients also often experience neuropsychiatric symptoms such as agitation. In severe cases, patients may require medications to manage their agitation.
Currently, no anti-agitation treatments are approved specifically for Alzheimer’s disease. However, a doctor may prescribe antipsychotics or antidepressants. Researchers are evaluating a few experimental treatments to manage agitation in Alzheimer’s disease patients.
AXS-05 is an oral medication that combines two compounds: bupropion and dextromethorphan. Dextromethorphan is able to control the activity of multiple neural signals that are thought to influence the cognition and behavior of people with Alzheimer’s. Bupropion also regulates the activity of these neural chemicals, and is thought to increase the stability and effectiveness of dextromethorphan. It is currently being tested in a Phase 3 trial.
AVP-786 is an oral therapy designed to be a second-generation version of Nuedexta, an approved treatment for Alzheimer’s and other neurological disorders. AVP-786, like Nuedexta, is a combination of dextromethorphan and quinidine, but also contains deuterium, an isotope of hydrogen. Scientists think that AVP-786’s penetration into the brain leads to the activation and repression of certain neuronal pathways, which help to ease agitation. It is currently in Phase 3 testing.
Brexpiprazole is a potential treatment to reduce agitation and other behavioral symptoms in people with Alzheimer’s disease and Alzheimer’s-associated dementia. The exact mechanism of action for brexpiprazole is still unknown. However, it is thought to work by changing the levels of serotonin and dopamine, which are naturally available neurotransmitters in the brain. It is currently in Phase 3 trials in Alzheimer’s patients.
Prazosin is a medication approved to treat high blood pressure. Research suggests it could also be used to relieve symptoms such as aggression in patients with moderate Alzheimer’s disease. Prazosin belongs to a class of drugs called alpha-blockers and competes with norepinephrine to bind to the alpha-1 adrenoreceptor, resulting in its reduced activation. This could potentially lead to less aggression in Alzheimer’s patients. It is being tested in Phase 2 trials.
Neurotransmitters are chemical messengers that carry signals between nerve cells. Two neurotransmitters are known to be involved in the development and progression of Alzheimer’s, including acetylcholine, which is involved in memory, judgment, and other thought processes; and glutamate, linked to information processing, storage, and retrieval. Another neurotransmitter called serotonin, which regulates appetite, mood, sleep, and sexual function, also has been linked to the disease. Several investigational therapies are being developed to target these neurotransmitters and potentially treat the disease.
DB105 is an investigational medication intended to treat memory loss as well as neuropsychiatric symptoms in Alzheimer’s, such as aggression, delusions, social withdrawal, and mood swings. It is designed to act on the alpha-2c adrenergic receptor on brain cells, which is thought to be involved in the release of neurotransmitters in the brain, especially in stressful situations. It was last studied in a Phase 2 trial for Alzheimer’s, but no results have been published yet.
Nuplazid (pimavanserin) is an oral therapy targeting serotonin that is being developed for managing psychotic symptoms such as psychosis, aggression, and agitation in Alzheimer’s disease patients. The U.S. Food and Drug Administration recently denied the approval of Nuplazid for Alzheimer’s patients, raising concerns about its effectiveness based on Phase 3 trial data. Next steps are currently being discussed.
PXT864 is an investigational oral combination being developed to treat neurodegenerative diseases including Alzheimer’s. It consists of two repurposed therapies: Kemstro (baclofen), a muscle relaxant and antispastic, and Campral (acamprosate calcium), a treatment for alcohol dependence. The experimental treatment is intended to work by restoring the balance between excitatory and inhibitory pathways in the brain. PXT864 was last studied in a Phase 2 trial.
Riluzole is an approved oral medication developed to slow disease progression in amyotrophic lateral sclerosis; it is now being investigated for Alzheimer’s. Riluzole increases the activity of a gene called EAAT2, which contains instructions for a protein that enables brain cells to reabsorb glutamate, preventing the accumulation of this neurotransmitter that can damage brain cells. A Phase 2/3 trial is currently underway.
SUVN-502 blocks the serotonin receptor 5-HT6, a protein responsible for binding the neurotransmitter serotonin, one of the key chemicals regulating the activity of brain cells. The blockage has been found to improve cognitive performance in animals. The potential therapy has completed testing in a Phase 2 trial.
Treatments That Target Beta-amyloid Protein
One of the hallmarks of Alzheimer’s disease is the formation of protein plaques and tangles between nerve cells. These are made of so-called beta-amyloid fragments that stick together and accumulate between nerve cells, disrupting their function. These beta-amyloid plaques are the focus of many experimental treatments currently in the pipeline.
ABvac40 is an investigational vaccine that consists of a fragment of beta-amyloid protein called beta-amyloid 40. It is designed to elicit an immune response against beta-amyloid plaques. In this way, it is hoped that brain cells will be protected and brain function will be preserved, or perhaps improved, following treatment. A Phase 2 trial is currently underway, with results expected in 2022.
Allopregnanolone is a neurosteroid that may help generate new brain cells. It is formed naturally in the brain when the hormone progesterone is broken down. A study has shown that Alzheimer’s patients have lower levels of allopregnanolone in their brains than people with healthy brains. A Phase 2 trial has been announced but is not yet recruiting patients.
ALZT-OP1 is a combined oral-inhaled therapy being developed to slow the progression of early Alzheimer’s This two-part therapy consists of a dry-powder inhaler containing cromolyn (designated ALZT-OP1a) and an oral pill containing ibuprofen (designated ALZT-OP1b). By targeting different parts of the immune system, ALZT-OP1 may be able to stop the destruction caused by neuroinflammation. Results from a Phase 3 trial are expected soon.
CAD106 is a vaccine being developed to potentially treat Alzheimer’s disease, or prevent it from developing, by attacking beta-amyloid plaque deposits in the brain. CAD106 is designed to stimulate the production of antibodies against beta-amyloid while avoiding an immune response against the recipient’s cells and tissues. A Phase 2/3 study is ongoing and expected to conclude in March 2025.
Crenezumab is a monoclonal antibody designed to bind to beta-amyloid proteins to prevent and break up their aggregation in existing plaques in Alzheimer’s disease, which is a hallmark of Alzheimer’s. This treatment mediates the clearance of beta-amyloid from the brain by microglia, a process called phagocytosis. Microglia are the immune cells of the central nervous system derived from bone marrow. A Phase 2 trial is ongoing.
Donanemab (LY3002813) is an antibody designed to stimulate the patient’s immune system to attack and destroy proteins in the brain that are believed to cause the neurodegeneration seen in Alzheimer’s. Researchers designed donanemab to bind to a form of beta-amyloid protein that already has aggregated into plaques and potentially clear them from the brain. It is currently being tested in a Phase 2 trial in early symptomatic Alzheimer’s.
Elayta is an oral medication being developed as a possible treatment for mild to moderate Alzheimer’s. Elayta is a small molecule that binds to a protein called the sigma-2 receptor. This receptor is found on the surface of many cells, including brain cells, and is thought to mediate the attachment of beta-amyloid to nerve cells. The potential therapy is currently in Phase 2 trials.
Gantenerumab is an investigational immunotherapy being developed to treat Alzheimer’s disease by potentially reducing beta-amyloid plaques in the brain. The treatment is administered as an injection under the skin. Gantenerumab is a fully human antibody, a protein that is designed to interact with a specific target. It binds to beta-amyloid, with a higher affinity for beta-amyloid clumps than free beta-amyloid that is circulating in the blood. It is currently being studied in Phase 3 trials.
PMN310 is an antibody that binds to the neurotoxic beta-amyloid aggregates, preventing additional beta-amyloid monomers from adding to them. Therefore, PMN310 may potentially neutralize toxic aggregates and prevent neurodegeneration. According to researchers, PMN310 has the potential for greater therapeutic potency than other beta-amyloid-directed antibodies for treating Alzheimer’s disease. It is still in the preclinical stages of development.
PQ912 is designed to inhibit glutaminyl cyclase (QC), a protein found at unusually high levels in affected regions of the brain in Alzheimer’s patients. QC promotes the production of a modified, toxic, and clumping form of beta-amyloid called pyroglutamate-abeta, which is the main component of the amyloid plaques found in patients’ brains. The potential therapy is being tested in Phase 2 trials.
Saracatinib is a potential treatment for Alzheimer’s disease that is intended to target and inhibit Fyn kinase, which causes the disruption of molecular pathways leading to the formation of insoluble beta-amyloid plaques. Scientists believe that through this mechanism, saracatinib could prevent or delay the progression of Alzheimer’s disease. A Phase 2 trial testing the potential therapy has been completed.
Solanezumab is a monoclonal antibody being developed to potentially treat mild cognitive impairment caused by Alzheimer’s disease. It is an antibody aimed at “cleaning” amyloid proteins from the blood and cerebrospinal fluid in an effort to prevent plaque formation. It is currently being tested in a Phase 3 trial in people who do not have memory loss but have evidence of beta-amyloid buildup in the brain.
UB-311 is a synthetic peptide vaccine for Alzheimer’s disease. A peptide is a short stretch of amino acids, which are the building blocks of proteins. The vaccine is designed to provoke an antibody response against beta amyloid, clearing it away without triggering potentially damaging inflammation. It completed a Phase 2 trial in people with mild Alzheimer’s.
Treatments That Target Tau Protein
Alzheimer’s disease is characterized by the protein plaques and tangles that are thought to be responsible for cell death and tissue loss in the brain. Tangles are twisted fibers of a protein called tau, which normally plays a role transporting nutrients through nerve cells. The tangled tau proteins cause the transport to be disrupted, leading to cells not getting enough nutrients and eventually dying. There are several experimental compounds being developed that target the tau protein tangles in Alzheimer’s disease.
AADvac1 works by inducing an immune response against tau. The protein agglomerates, or clumps together, and forms so-called neurofibrillary tangles inside the brain cells. These tangles disrupt the normal functioning of neurons and were identified as one of the primary reasons for cognitive impairment in people with Alzheimer’s disease. A Phase 2 trial has been completed testing AADvac1.
ABBV-8E12 is an anti-tau antibody being developed to treat Alzheimer’s disease and progressive supranuclear palsy, which are both tauopathies. It is a recombinant, humanized anti-tau antibody that recognizes and binds to the abnormal tau aggregates, potentially blocking their spread from neuron to neuron and limiting the severity of the disease. A Phase 2 trial testing the potential therapy in early Alzheimer’s patients is currently ongoing.
ACI-35 is an investigational anti-tau vaccine being developed to potentially treat Alzheimer’s disease. ACI-35 is a liposome-based vaccine consisting of a synthetic peptide antigen and a liposomal anchor, to mimic the pathological shape of the tau protein. In this way, it activates the immune system to produce antibodies that selectively target the misfolded and pathogenic forms of the tau protein. A Phase 1/2 trial is currently recruiting people with early Alzheimer’s.
LMTX is a tau aggregation inhibitor, which is aimed at reducing levels of the abnormal tau protein. The active component of LMTX, methylthioninium chloride, binds preferentially to the abnormal tau and removes the damaging tangles. Through this mechanism, LMTX aims to potentially slow the progression of the disease by reducing the tau-mediated damage in the brain. It is currently in Phase 3 testing.
RO7105705 is an experimental immunotherapy being developed to potentially treat Alzheimer’s disease. It is an antibody that recognizes abnormal forms of tau and aims to block their spread from one cell to the other. A Phase 2 trial in people with moderate Alzheimer’s is currently underway.
Zagotenemab is an antibody designed to bind to and neutralize tau protein tangles, hopefully slowing or stopping the worsening of Alzheimer’s disease. The potential therapy is currently being tested in a Phase 2 trial in people with early symptomatic Alzheimer’s.
Treatments With Other Modes of Action
While most experimental treatments being developed target beta-amyloid plaques and tau protein tangles, several other potential therapies with different modes of action are also being developed to treat either the underlying cause of Alzheimer’s or its related symptoms.
Anavex 2-73 is an investigational oral therapy being developed to slow the progression of Alzheimer’s disease. It targets protein misfolding and oxidative stress by binding to a protein called sigma-1, which is known to modulate cellular processes relevant to neurodegeneration. A Phase 2b/3 trial is ongoing and still enrolling people with early Alzheimer’s.
Carvedilol is an approved medication for the treatment of high blood pressure and heart failure that is now being investigated for the treatment of memory decline in patients with mild Alzheimer’s disease. Experiments in mouse models suggest that it interferes with the buildup of beta-amyloid fragments in the brain. A Phase 4 trial in Alzheimer’s patients was completed, but results showed no significant benefits of the treatment.
Curcumin is a bright yellow plant extract obtained from turmeric. A mainstay of traditional Chinese and Indian herbal medicines, curcumin is a polyphenol thought to have anti-inflammatory and antioxidant effects. It has been shown to ease Alzheimer’s disease-like symptoms in mice. An ongoing Phase 2 trial is investigating the combined benefits of curcumin and yoga in people with mild cognitive impairment.
Leukine (sargramostim) is an immune system stimulator that works to boost the number and function of white blood cells to reduce the risk of infection. It is used to treat conditions in which white blood cell counts are low, such as in certain types of leukemia or in patients who received a bone marrow transplant. Leukine also is being investigated as a potential treatment for cognitive problems related to Alzheimer’s. A Phase 2 trial has been completed testing the therapy in Alzheimer’s patients.
Liraglutide is a treatment for type 2 diabetes that has the potential to relieve the symptoms of Alzheimer’s disease, and possibly slow or stop the progression of the disease. Liraglutide is an analog of glucagon-like peptide 1 (GLP-1), a hormone that stimulates insulin signaling. Increased insulin signaling is thought to improve the transport of glucose in the brain and potentially reduce nerve cell death. A Phase 3 trial is currently being planned.
Nicotinamide is a form of vitamin B3 that scientists are looking at as a potential treatment for Alzheimer’s disease. They believe nicotinamide may have neuroprotective effects, meaning it may help protect brain cells from Alzheimer’s damage. A Phase 2 trial is currently underway testing the potential therapy in people with mild Alzheimer’s.
Insulin, administered via a nasal spray, is being investigated as a treatment for Alzheimer’s disease. While insulin is best known for its role in regulating blood sugar, it also is thought to play a role in Alzheimer’s, in that reduced levels of insulin and insulin signaling have been seen in patients’ brains. It has completed a Phase 2/3 trial in people with mild Alzheimer’s.
Piromelatine is an oral treatment that improves sleep by modifying different chemical systems in the brain. The compound is being investigated for its potential to improve cognitive function and slow the progression of Alzheimer’s disease by promoting better sleep. It has been studied in a Phase 2 trial in Alzheimer’s patients.
Resveratrol is a compound that occurs naturally in certain foods, including the skin of grapes and red wine. It is also found in grape juice, peanuts, cocoa, and berries such as blueberries and cranberries. Previous studies have shown that it could possibly lower risk of dementia. A Phase 1 trial is testing its effects in people with mild cognitive impairment and prediabetes or type 2 diabetes.
S-equol is an oral medicine initially developed for treating the symptoms of menopause and benign prostate hyperplasia. It is now being investigated to potentially treat mitochondrial dysfunction in Alzheimer’s. Faulty mitochondria have been observed in the disease and are thought to contribute to beta-amyloid plaque deposits in nerve cells. A Phase 1/2 trial is currently underway and still recruiting.
Sumifilam is an experimental small molecule that is designed to ease the cognitive symptoms of Alzheimer’s. It targets misfolded filamin A protein. By binding to this filamin A, the compound is aimed at restoring the protein’s function, potentially alleviating disease symptoms. A Phase 2 trial is currently recruiting people with mild to moderate Alzheimer’s.
T3D-959 is an investigational small molecule that works by activating two proteins known as PPAR delta and PPAR gamma, which are known to regulate blood sugar and triglyceride (fat) levels. It is hoped that by acting on the PPAR proteins, T3D-959 may correct age-related metabolic dysfunctions and ease disease symptoms. A Phase 2 trial is currently recruiting patients with mild to moderate Alzheimer’s.
Thiethylperazine, sold for years under the brand name Torecan to relieve nausea and vomiting, is currently being investigated for Alzheimer’s. Thiethylperazine is a small molecule that can activate a protein called MRP1 in the brain. It is thought that through the increased activation of MRP1, thiethylperazine can promote the removal of toxic beta-amyloid to potentially reduce the damage it causes to the nerve cells. A Phase 2 trial is currently underway in Germany.
Telmisartan, sold under the brand name Micardis, is a high blood pressure medicine now being investigated as a treatment for Alzheimer’s. Researchers believe telmisartan can slow the progression of Alzheimer’s by controlling blood flow, protecting capillary blood vessels, and reducing plaque formation in the brain. The therapy is being tested in both Phase 1 and 2 trials in different patient populations.
TPI 287 is a medication being developed for the treatment of Alzheimer’s disease, progressive supranuclear palsy, and corticobasal syndrome. TPI 287 is able to reach the brain and stabilizes microtubules inside nerve cells. It is hoped that the medicine can stop, or even reverse, the course of Alzheimer’s disease. A Phase 1 trial testing TPI 287 has been completed.
Xanamem is designed to reduce levels of the steroid hormone cortisol in the brain. It does this by blocking an enzyme called 11-beta‐hydroxysteroid dehydrogenase type 1, which converts inactive cortisone to cortisol, the active hormone. Inhibiting this enzyme may slow or prevent cognitive decline. A Phase 2 trial has been completed in patients with mild dementia due to Alzheimer’s.