Despite the great need for more effective Alzheimer’s disease (AD) treatments, no really new or different medication has been approved by the FDA for this purpose in over a decade.

Recently, Dr. Jeffrey Cummings and his colleagues took a bird’s eye view of the current drug development pipeline.1 They identified 105 distinct agents being tested in 2017, of which about one quarter were in phase III studies, the final round of testing before the FDA judges their safety and efficacy.

Disease-Modifying Therapies

The majority of the drugs in testing are called disease-modifying therapies (DMTs). This means their primary goal is not specifically to reduce current symptoms but rather to improve outcome over the longer term by changing the course of the disease. Most of the DMTs being investigated are designed to reduce existing brain amyloid levels or to decrease its production. This target continues to dominate drug development because the “amyloid hypothesis” is still considered a likely explanation for AD’s damaging effects. The amyloid hypothesis proposes that a cell membrane protein called amyloid precursor protein (APP) is clipped by enzymes, resulting in small toxic amyloid protein fragments (beta amyloid), which disrupt communication between nerve cells, and also clump together in the brain to form plaques. The plaques incite a local inflammatory reaction, which kills nerve cells.

Passive Immunotherapy

Passive immunotherapies, which are intravenously injected antibody solutions designed to target and remove beta amyloid from the blood and/or brain, continue to be investigated despite some significant failures.

Aducanumab is unusual among the antibodies still in testing because it targets more than one variety of beta amyloid.

Additional drugs of interest in this class include crenezumab, gantenerumab, and others. Solanezumab, at one time considered a hopeful contender in the drug race, has recently been judged ineffective as a dementia treatment. Its value as a preventive treatment continues to be explored.

BACE Inhibitors

To reduce production of beta amyloid, researchers have also developed drugs that inhibit the activity of an enzyme called beta-amyloid cleaving enzyme (BACE). Advances in the tools for identifying drug candidates have made it easier to discover BACE inhibitors that can cross the blood-brain barrier and reduce amyloid levels in the spinal fluid and brain.

Approximately ten BACE inhibitors are currently being tested in phase II and III trials. Investigators continue to be hopeful that the clinical value of a BACE inhibitor will be demonstrated, though one phase III trial has already been terminated for lack of efficacy. Among the BACE inhibitors in testing are verubecestat, LY3314814, LY3202626, CNP520, E2609, and others.

Other Treatment Avenues

Medications that counter other possible disease-causing mechanisms are also being explored, though fewer clinical trials are looking at DMTs based on non-amyloid theories.

Tau

In addition to beta-amyloid plaques, neurofibrillary tangles are the other hallmark of Alzheimer’s disease. The tangles consist of insoluble twisted fibers found inside the brain’s nerve cells. They primarily consist of a protein called tau, which forms part of a structure called a microtubule. The microtubule helps transport nutrients and other important substances from one part of the nerve cell to another. In Alzheimer’s disease, the tau protein is abnormal and the microtubule structures collapse.

Among the therapies that target tau protein pathology are TRx0237, AADvac1, ABBV-8E12, RO7105705, TPI-287, and others.

Anti-Inflammatory Medications

Supporters of the inflammatory theory of AD are studying anti-inflammatory medications including agents such as TTP488, formoterol, probucol, telmistartan, and others.

Protecting Brain Cells

A group of medications in testing that are neuroprotective through a variety of other actions includes BI409306, bryostatin, candesartan, CPC201, rasagaline, riluzole, simvastatin, sargramostim, and insulin, among others. Explanation of each drug’s mechanism of action is beyond this discussion but can be found at www.clinicaltrials.gov.

Symptom-Controlling Treatments

Although disease modification is an important goal, patients and clinicians still currently need symptom-controlling medications. Some of the symptomatic agents in testing aim to enhance cognition while others target reduction of non-cognitive behavioral symptoms.

Enhancing Cognition

The cognitive-enhancing agents include medications with a variety of actions different from those of the currently approved medications for Alzheimer’s disease. Enhancing cognition may improve memory, language, thinking, and judgment.

Among these are nicotine and nicotinamide, ginkgo, allogpregnanolone, curcumin, riluzole, candesartan and insulin.

Non-Cognitive Enhancing Agents

Many of the agents being tested for alleviating non-cognitive behavioral symptoms are repurposed drugs already in use for other indications. Non-cognitive behavioral symptoms include apathy, agitation, and sleep disturbances. Examples of these medications include the antidepressants escitalopram and mirtazapine, the cannabinoids nabilone and dronabinol, the anticonvulsants carbamazepine and levetiracetam, the novel antipsychotic pimavanserin, the combination of dextromethorphan and quinidine that was previously approved for treatment of pseudobulbar affect (uncontrollable episodes of emotions, such as laughing or crying), the mood regulator lithium, and the stimulant methylphenidate. A few additional new agents affect specific neurotransmitter levels in various ways. A neurotransmitter is a chemical messenger that allows nerve cells to communicate with one another and with other types of cells in the body.

Non-Medication Treatments

Medications, of course, represent only one of the areas in which researchers are attempting to overcome the effects of AD. In addition to clinical drug trials, ongoing studies are examining non-medication treatments such as light therapy, transcranial direct current stimulation, transcranial magnetic stimulation, acupuncture and electro-acupuncture, electroconvulsive therapy and deep brain stimulation.

Special diets offer another hopeful route to improving brain function in people with AD.

Psychosocial therapies are being studied to identify and improve effective treatment approaches for sleep disruption and other behavioral disturbances in Alzheimer’s disease.

Cognitive therapy for both cognitively impaired individuals and for assisting their caregivers is another area of exploration that may teach us how to support those affected by AD.

Why have we not conquered, or more effectively weakened, the grip that AD has on our aging population? There are some formidable obstacles in the way of success. We know what causes many other diseases, but the real cause of AD remains a matter of debate. The amyloid cascade theory, which blames the toxic beta-amyloid protein for the signs and symptoms of the disease, has led to the development of many medications, but as yet none of these has proven very effective. Treatment approaches coming from other disease models have been limited, but some new medications in testing are based on competing theories that may give us some valuable insights.

To complicate matters further, many new medications are tested in animal models that provide results which do not always translate into benefits for humans. Even if a promising medication is found, human testing and FDA review typically take more than ten years to complete. The majority of AD medications have been developed and tested by the pharmaceutical industry, but the cost of drug development is so high that one major company recently stopped looking for new AD drugs. Federal grant support for AD research remains very limited.

An additional and very fundamental roadblock to AD drug development is identification and recruitment of volunteers willing to take an experimental medication and undergo testing, often for a trial that lasts more than a year. These days, participation in AD trials requires careful screening that limits participants to people with a proven diagnosis and at a suitable stage of the illness. It is estimated that more than 54,000 participants will be needed just to complete the trials currently underway. Although that number represents only about 1 percent of people in the US with AD, it still reflects a challenging goal that can be met only through collaboration of patients, caregivers, clinicians, researchers, industry and funding agencies.