What’s New in the Alzheimer’s Treatment Pipeline?

Learn about potential new treatments for Alzheimer’s disease that may help manage current symptoms, but also improve outcome over the longer term by changing the course of the disease.

The search for new medications that are both safe and effective weapons in the fight against Alzheimer’s disease has already demanded the collaboration of thousands of researchers and hundreds of thousands of willing subjects. But it is far from over! Since 1998, 146 drugs have been tested and rejected. Only four drugs have made it through the rigorous clinical trial process that precedes approval by the Food and Drug Administration (FDA). The approved drugs have modest symptom-reducing effects, but they do not alter the eventual course of Alzheimer’s disease.

A Recent Disappointment and Renewed Hope

That is why so many patients, caregivers, researchers, and pharmaceutical executives groaned with disappointment in March of this year, when an especially hopeful new medication, aducanumab, was deemed a failure. Plans were made to shut down the two large trials investigating its potential after a few additional months. Aducanumab belongs to the class of drugs known as the anti-amyloid monoclonal antibodies. These molecules, manufactured biologically and injected into research subjects with early Alzheimer’s disease, are like magic bullets targeted at toxic amyloid similar to the way that our own antibodies attack infectious bacteria. In early trials, aducanumab appeared to have disease-modifying properties. When administered to people in an early stage of Alzheimer’s disease, it not only reduced brain amyloid content, it also appeared to delay cognitive decline. No wonder its apparent failure was so upsetting.

Using additional data gathered during the final months of study, Biogen revised its earlier assessment. In 2020, an application for approval of aducanumab was submitted to the FDA, seeking permission to market it as an Alzheimer’s disease treatment. In November of 2020, a panel of experts concluded that the clinical data did not support the approval of aducanumab.  The FDA’s final decision is anticipated late in March of 2021.

Aducanumab is only one of an estimated 132 Alzheimer medications currently being tested in 670 trials. An overview of these new soldiers in the war against Alzheimer’s was published recently by Dr. Jeffrey Cummings and his colleagues.¹ The identification of new targets and new drug mechanisms has researchers busy and hopeful.

Three Areas of Alzheimer’s Medication Research

Disease-Modifying Biologics

Disease-modifying biologics are medications produced from living organisms or containing components of living organisms. Vaccines and antibodies are two examples of biologics. These drugs are often large molecules designed to control the actions of other genes, proteins, immune responses, or other cellular processes. The monoclonal antibodies targeting the two hallmarks of Alzheimer’s disease, toxic amyloid and the malfunctioning tau protein, belong to this class. In addition to aducanumab, two other anti-amyloid antibodies still being investigated are solanezumab and gantenerumab.

Disease-Modifying Small Molecules

Disease-modifying small molecules are designed to control biologic processes, are less complex structures that do not originate in living organisms. They are developed in an effort to interfere with multiple disease pathways. Earlier small molecule Alzheimer’s treatments such as the cholinesterase inhibitors and memantine did not modify the course of the disease. Newer small molecule therapies are designed to alter aspects of Alzheimer’s pathology through various mechanisms. Some of these molecules reduce inflammation. Others nurture the growth of synapses, interfere with toxic activities of enzymes, enhance neurotransmission, or improve cellular energy production. Insulin-related molecules, dietary components such as curcumin and omega-3 fatty acids, and tau-active agents such as methylene blue belong to this group.

Symptom-Reducing Small Molecules

Finally, there is a class of symptom-reducing small molecules. Many of these molecules target the non-cognitive behaviors that make caregiving more burdensome. Marijuana components such as nabilone or dronabinol; sleep-enhancing agents such as lemborexant, piromelatine and zolpidem; antidepressants such as escitalopram and mirtazapine; and antipsychotics including brexpiprazole and pimavanserin fall into this category.

Non-Medication Alzheimer's Research

Medications are, of course, only one approach to managing the devastating effects of Alzheimer’s disease. In other areas of research, non-pharmacologic trials continue to explore the effects of treatments such as light therapy, transcranial direct current stimulation, transcranial magnetic stimulation, acupuncture, electroconvulsive therapy, and deep brain stimulation. Special diets, psychosocial therapies, and physical activity are additional areas of inquiry. Psychotherapy and education of caregivers are also being investigated as ways of improving the quality of life for both caregivers and patients. The importance, too, of lifestyle factors has increasingly been recognized and this is being systematically researched.

Summary

Much is known about Alzheimer’s disease, but the underlying cause remains obscure. This makes it more difficult to find therapies capable of slowing its course. The amyloid cascade theory, which attributes the disease’s effects to the accumulation of toxic amyloid protein, continues to generate new agents and studies. But additional disease mechanisms are being explored more actively now and may lead to valuable additional or alternate treatment approaches. In order to conquer this disease, scientists, clinicians, research subjects, caregivers, funding agencies, and pharmaceutical companies will need to join their forces. With such a cooperative effort, great strides have already been made in reducing the ravages of cancer, heart disease, stroke, and infection, among other diseases. Many researchers and clinicians envision a future in which the toll that Alzheimer’s disease currently takes will be greatly reduced by a healthier lifestyle and improved therapies.